Anti-androgenic pyrrolidines with tumor-inhibiting action

ABSTRACT

This invention relates to anti-androgenic N-[ω-[3-[4-cyano-3-(trifluoromethyl)-phenyl]-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl]alkyl]-substituted pyrrolidines of general formula I,  
                 
with a strongly pronounced antiproliferative profile of action; process for the production of the compounds of general formula I, pharmaceutical preparations and the use for the production of pharmaceutical agents.

This invention relates to anti-androgenicN-[ω-[3-[4-cyano-3-(trifluoromethyl)-phenyl]-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl]alkyl]-substitutedpyrrolidines, with a strongly pronounced antiproliferative actionprofile, process for their production, as well as pharmaceuticalpreparations that contain the pyrrolidines according to the inventionand their use for the production of pharmaceutical agents.

In industrialized countries, prostate cancer, after lung cancer, is thesecond main cause of death by cancer in men. In men over 55 years ofage, 4% of all deaths can be attributed to a prostate tumor disease, andit is expected that the proportion in men over 80 increases to up to 80%of deaths. The death rate is still relatively low, but it increasesyearly by about 14%. The number of men in whom a prostate tumor wasdiagnosed has increased by 30% in recent years, which can be attributedless to an increasing number of new diseases but rather that thepopulation is generally older, that diagnostic processes have improvedand that systematic screening programs were introduced (E. J. Small, D.M. Reese, Curr. Opi. Oncol. 2000, 12, 265-272).

The prostate tumor grows in an androgen-dependent manner in earlystages. As long as the tumor is locally limited to the prostate, it canbe removed by surgical intervention or by radiation therapy, wherebythese methods are associated with corresponding risks. In the cases inwhich the tumor is no longer locally limited and has already formedmetastases, the tumor is treated palliatively by reduction of thetestosterone level in the blood. This is carried out either surgicallyby castration or medicinally by treatment with anti-androgens(bicalutamide, cyproterone acetate, flutamide), LHRH-agonists(buserelin, zoladex), LHRH-antagonists (cetrorelix) or 5α-reductaseinhibitors (finasteride). Since the adrenal androgen synthesis remainsunaffected in a surgical cas-formed (S. Leewansangtong, E. D. Crawford,Endocrine-Related Cancer 1998, 5, 325-339). This treatment, however, hasonly temporary success, since after at the latest two years, itgenerally results in renewed growth of the tumor, which in most cases isthen hormone-independent (L. J. Denis, K. Griffith, Semin. in Surg. Onc.2000, 18, 52-74). Despite intensive research in the last 50 years, upuntil now there has been no effective treatment against these advancedstages. The 5-year survival rate in these patients is less than 15%.

There are different indications that show that the androgen receptorplays an important role in the development and the growth of theprostate tumor not only in the early hormone-dependent stages of thetumor progression, but also in late hormone-independent stages of thetumor progression.

The androgen receptor belongs to the family of steroid hormone receptorsthat act as transcription factors. The androgen receptor bindsandrogens, by which it is stabilized and protected from a quickproteolytic degradation. After hormone bonding, it is transported intothe nucleus, where it activates certain genes by binding to so-calledandrogen-responsive DNA elements that are in promoter regions (D. J.Lamb et. al. Vitam. Horm. 2001, 62, 199-230).

Studies on prostate tumors show that in 30% of advanced tumors, anamplification of the androgen receptor gene locus was detected. In othercases, a number of mutations were found in the androgen receptor gene,which are localized in various domains of the androgen receptor moleculeand result in altered receptor properties. Mutated receptors can eitherhave a higher affinity for androgens, be constitutively active, changetheir ligand specificity, so that they are activated by other steroidhormones or even anti-androgens, be activated via interactions withmolecules from other growth-promoting signal-transmitting methods,change the interaction with cofactors, or activate other target genes(J. P. Elo, T. Visakorpi, Ann. Med. 2001, 33, 130-41).

The identification of anti-androgens, which inhibit not only the naturalandrogen receptor but also its mutated forms and have an enhancedantiproliferative effect on tumor cells, would presumably be veryhelpful in treating prostate tumors in various stages. Such compoundscan significantly change the period until the tumor growth recurs.

Studies with nonsteroidal anti-androgens have shown that they haveadvantages compared to the steroidal compounds and are therefore to bepreferred. Thus, with nonsteroidal compounds, a more selective actionwith fewer adverse side effects can be achieved. In contrast to thesteroidal anti-androgens, the known nonsteroids bicalutamide andflutamide lack, e.g., the progestagenic activity, and in addition, theiruse results in an increase in the testosterone level in the serum, whichclinically could result in development of potency (P. Reid, P. Kantoff,W. Oh, Investigational New Drugs 1999, 17, 271-284).

Nonsteroidal anti-androgens are described in U.S. Pat. No. 5,411,981 orU.S. Re. Pat No. 35956 (phenylimidazolidine derivatives), in WO 97/00071(specifically substituted phenyldimethyl hydantoins as well as theirimino- or thione derivatives), in WO 00/37430 (phenylalanine, phenylhydantoins as well as phenyl ureas), in WO 01/58855 (amino-propanilides)and in EP 1122242 (substituted cyanophenylpiperazines).

U.S. Re. Pat. No. 35956 describes, i.a.,[4-cyano-3-(trifluoromethyl)phenyl]-substituted thiohydantoins with ashort-chain, terminally substituted radical, whereby in the case of thechain, this is preferably a C₁-C₄-chain.

The compounds that are explicitly disclosed in U.S. Re. Pat. No. 35956have an anti-androgenic action, but only a slightly antiproliferativeaction in cells that originate from human prostate cancers.

For an effective therapy of androgen-dependent tumors and/or otherproliferative diseases, an additional antiproliferative action isnecessary.

The object of this invention therefore consists in making availableorally bioavailable anti-androgenic compounds with increasedantiproliferative action that can inhibit the growth ofandrogen-dependent benign or malignant tumors or alleviate or healandrogen-dependent proliferative diseases.

This object is achieved according to the invention by theN-[ω-[3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl]alkyl]-substitutedpyrrolidines of general formula I:

-   -   in which    -   n can mean an integer between 6 and 9,    -   R¹ and R², independently of one another, can mean a hydrogen        atom, an unbranched C₁-C₄-alkyl group, a branched C₃-C₅-alkyl        group, an unbranched hydroxy-C₁-C₄-alkyl group, a branched        hydroxy-C₃-C₅-alkyl group, an unbranched        C₁-C₄-alkoxy-C₁-C₄-alkyl group, a branched        C₁-C₄-alkoxy-C₃-C₅-alkyl group, an unbranched        C₁-C₄-alkanoyloxy-C₁-C₄-alkyl group, a branched        C₁-C₄-alkanoyloxy-C₃-C₅-alkyl group, a (pyrrolidin-1-yl)methyl        group, a carboxy group, a C₁-C₄-alkoxycarbonyl group or an        aminocarbonyl group,    -   or    -   R¹ and R² together can mean a 2-hydroxypropane-1,3-diyl bridge;    -   R³ can mean a hydrogen atom or a hydroxy group.

It was found that the antiproliferative action of compounds of theN-[3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethylthiohydantoin typecan be increased, surprisingly enough, while retaining anti-androgenicactivity, if the N-1-nitrogen carries a pyrrolidin-1-ylalkylsubstituent. The compounds according to the invention are distinguishedby an alkylene chain of a defined length range, which connects thepyrrolidine nucleus to the thiohydantoin nucleus. Depending on thecombination of the heterocyclic end group with the length of thealkylene chain that connects the latter with the thiohydantoin nucleus,a more or less pronounced additional effect that results in thedestabilization of the androgen receptor can occur.

This invention comprises a process for the production of the compoundsof general formula I according to the invention, in which compounds ofgeneral formula II

-   -   in which    -   n can mean an integer between 6 and 9,

X can mean a leaving group,are reacted in the presence of an organic base with compounds of generalformula III

-   -   in which    -   R₁ and R², independently of one another, can mean a hydrogen        atom, an unbranched C₁-C₄-alkyl group, a branched C₃-C₅-alkyl        group, an unbranched hydroxy-C₁-C₄-alkyl group, a branched        hydroxy-C₃-C₅-alkyl group, an unbranched        C₁-C₄-alkoxy-C₁-C₄-alkyl group, a branched        C₁-C₄-alkoxy-C₃-C₅-alkyl group, an unbranched        C₁-C₄-alkanoyloxy-C₁-C₄-alkyl group, a branched        C₁-C₄-alkanoyloxy-C₃-C₅-alkyl group, a (pyrrolidin-1-yl)methyl        group, a carboxy group, a C₁-C₄-alkoxycarbonyl group or an        aminocarbonyl group,    -   or    -   R¹ and R² together can mean a 2-hydroxypropane-1,3-diyl bridge;    -   R³ can mean a hydrogen atom or a hydroxy group.

Alkenyl chain —(CH₂)_(n)— is the n-hexylene, n-heptylene, n-octylene orn-nonylene group.

The unbranched hydroxy-C₁-C₄-alkyl group can be ahydroxymethyl-(HOCH₂—), 2-hydroxyethyl-(HOCH₂CH₂—),1-hydroxyethyl-[CH₃CH(OH)—], 3-hydroxypropyl-(HOCH₂CH₂CH₂—),2-hydroxypropyl-[CH₃CH(OH)CH₂CH₂—], 21-hydroxypropyl-[CH₃CH₂CH(OH)—],4-hydroxybutyl-(HOCH₂CH₂CH₂CH₂—), 3-hydroxybutyl-[CH₃CH(OH)CH₂CH₂—],2-hydroxybutyl-[CH₃CH₂CH(OH)CH₂—] or 1-hydroxybutyl [CH₃CH₂CH₂CH(OH)]group.

The branched hydroxy-C₃-C₅-alkyl group can be a1-hydroxy-1-methylethyl-[(CH₃)₂C(OH)—],2-hydroxy-1-methylethyl-[HOCH₂CH(CH₃)-],1-hydroxy-1-methylpropyl-[CH₃CH₂C(CH₃)(OH)—],2-hydroxy-1-methylpropyl-[CH₃CH(OH)CH(CH₃)-],3-hydroxy-1-methylpropyl-[HOCH₂CH₂CH(CH₃)-],1-(hydroxymethyl)propyl-[CH₃CH₂C(CH₂OH)—],1-hydroxy-2-methylpropyl-[(CH₃)₂CHCH(OH)—],2-hydroxy-2-methylpropyl-[CH₃C(OH)(CH₃)CH₂—],23-hydroxy-2-methylpropyl-[HOCH₂CH(CH₃)CH₂—],21-(hydroxymethyl)butyl-[CH₃CH₂CH₂CH(CH₂OH)—],1-hydroxy-1-methylbutyl-[CH₃CH₂CH₂C(CH₃)(OH)—],2-hydroxy-1-methylbutyl-[CH₃CH₂CH(OH)CH(CH₃)-],3-hydroxy-1-methylbutyl-[CH₃CH(OH)CH₂CH(CH₃)—],4-hydroxy-1-methylbutyl-[HOCH₂CH₂CH₂CH(CH₃)—],3-hydroxy-1-ethylpropyl-[HOCH₂CH₂CH(CH₂CH₃)—],2-hydroxy-1-ethylpropyl-[CH₃CH(OH)CH(CH₂CH₃)—],1-hydroxy-1-ethylpropyl-[CH₃CH₂C(CH₂CH₃)(OH)—],1-hydroxy-3-methylbutyl-[CH₃CH(CH₃)CH₂CH(OH)—],2-hydroxy-3-methylbutyl-[(CH₃)₂CHCH(OH)CH₂—],23-hydroxy-3-methylbutyl-[CH₃C(CH₃)(OH)CH₂CH₂—],4-hydroxy-3-methylbutyl-[HOCH₂CH(CH₃)CH₂CH₂—],21-(hydroxymethyl)-1-methylpropyl-[CH₃CH₂C(CH₃)(CH₂OH)—],2-hydroxy-1,1-dimethylpropyl-[CH₃CH(OH)C(CH₃)₂—],23-hydroxy-1,1-dimethylpropyl-[HOCH₂CH₂C(CH₃)₂—],1-(hydroxymethyl)-2-methylpropyl-[(CH₃)₂CHCH(CH₂OH)—],1-hydroxy-1,2-dimethylpropyl-[(CH₃)₂CHC(OH)(CH₃)—],2-hydroxy-1,2-dimethylpropyl-[(CH₃)₂C(OH)CH(CH₃)—],3-hydroxy-1,2-dimethylpropyl-[HOCH₂CH(CH₃)CH(CH₃)—],1-hydroxy-2,2-dimethylpropyl-[(CH₃)₃CCH(OH)—],3-hydroxy-2,2-dimethylpropyl-[HOCH₂C(CH₃)₂CH₂—],21-hydroxy-2-methylbutyl-[CH₃CH₂CH(CH₃)CH(OH)—],2-hydroxy-2-methylbutyl-[CH₃CH₂C(CH₃)(OH)CH₂—],23-hydroxy-2-methylbutyl-[CH₃CH(OH)CH(CH₃)CH₂—],24-hydroxy-2-methylbutyl-[HOCH₂CH₂CH(CH₃)CH₂—] or3-hydroxy-2-ethylpropyl-[HOCH₂CH(CH₂CH₃)CH₂—] group.

The unbranched C₁-C₄-alkoxy-C₁-C₄-alkylene group can be analkoxymethyl-(AlkOCH₂—), 2-alkoxyethyl-(AlkOCH₂CH₂—),1-alkoxyethyl-[CH₃CH(OAlk)—], 3-alkoxypropyl-(AlkOCH₂CH₂CH₂—),2-alkoxypropyl-[CH₃CH(OAlk)CH₂CH₂—], 21-alkoxypropyl-[CH₃CH₂CH(OAlk)—],4-alkoxybutyl-(AlkOCH₂CH₂CH₂CH₂—), 3-alkoxybutyl-[CH₃CH(OAlk)CH₂CH₂—],2-alkoxybutyl-[CH₃CH₂CH(OAlk)CH₂—] or 1-alkoxybutyl [CH₃CH₂CH₂CH(OAlk)—]group.

The branched C₁-C₄-alkoxy-C₃-C₅-alkyl group can be a1-alkoxy-1-methylethyl-[(CH₃)₂C(OAlk)—],2-alkoxy-1-methylethyl-[AlkOCH₂CH(CH₃)—],1-alkoxy-1-methylpropyl-[CH₃CH₂C(CH₃)(OAlk)—],2-alkoxy-1-methylpropyl-[CH₃CH(OAlk)CH(CH₃)—],3-alkoxy-1-methylpropyl-[AlkOCH₂CH₂CH(CH₃)—],1-(alkoxymethyl)propyl-[CH₃CH₂C(CH₂OAlk)—],1-alkoxy-2-methylpropyl-[(CH₃)₂CHCH(OAlk)—],2-alkoxy-2-methylpropyl-[CH₃C(OAlk)(CH₃)CH₂—],3-alkoxy-2-methylpropyl-[AlkOCH₂CH(CH₃)CH₂—],1-(alkoxymethyl)butyl-[CH₃CH₂CH₂CH(CH₂OAlk)—],1-alkoxy-1-methylbutyl-[CH₃CH₂CH₂C(CH₃)—],2-alkoxy-1-methylbutyl-[CH₃CH₂CH(OAlk)CH(CH₃)—],3-alkoxy-1-methylbutyl-[CH₃CH(OAlk)CH₂CH(CH₃)—],4-alkoxy-1-methylbutyl-[AlkOCH₂CH₂CH₂CH(CH₃)—],3-alkoxy-1-ethylpropyl-[AlkOCH₂CH₂CH(CH₂CH₃)—],2-alkoxy-1-ethylpropyl-[CH₃CH(OAlk)CH(CH₂CH₃)—],1-alkoxy-1-ethylpropyl-[CH₃CH₂C(CH₂CH₃)(OAlk)—],1-alkoxy-3-methylbutyl-[CH₃CH(CH₃)CH₂CH(OAlk)—],2-alkoxy-3-methylbutyl-[(CH₃)₂CHCH(OAlk)CH₂—],3-alkoxy-3-methylbutyl-[CH₃C(CH₃)(OAlk)CH₂CH₂—],4-alkoxy-3-methylbutyl-[AlkOCH₂CH(CH₃)CH₂CH₂—],1-(alkoxymethyl)-1-methylpropyl-[CH₃CH₂C(CH₃)(CH₂OAlk)—],2-alkoxy-1,1-dimethylpropyl-[CH₃CH(OAlk)C(CH₃)₂—],3-alkoxy-1,1-dimethylpropyl-[AlkOCH₂CH₂C(CH₃)₂—],1-(alkoxymethyl)-2-methylpropyl-[(CH₃)₂CHCH(CH₂OAlk)—],1-alkoxy-1,2-dimethylpropyl-[(CH₃)₂CHC(OAlk)(CH₃)—],2-alkoxy-1,2-dimethylpropyl-[(CH₃)₂C(OAlk)CH(CH₃)—],3-alkoxy-1,2-dimethylpropyl-[AlkOCH₂CH(CH₃)—CH(CH₃)—],1-alkoxy-2,2-dimethylpropyl-[(CH₃)₃CCH(OAlk)—],3-alkoxy-2,2-dimethylpropyl-[AlkOCH₂C(CH₃)₂CH₂—],1-alkoxy-2-methylbutyl-[CH₃CH₂CH(CH₃)CH(OAlk)—],2-alkoxy-2-methylbutyl-[CH₃CH₂C(CH₃)(OAlk)CH₂—],3-alkoxy-2-methylbutyl-[CH₃CH(OAlk)CH(CH₃)CH₂—],4-alkoxy-2-methylbutyl-[AlkOCH₂CH₂CH(CH₃)CH₂—] or3-alkoxy-2-ethylpropyl-[AlkOCH₂CH(CH₂CH₃)CH₂—] group.

The C₁-C₄-alkoxy group can be, for example, a methoxy-, ethoxy-,n-propoxy-, iso-propoxy-, n-butoxy-, sec-butoxy-, iso-butoxy- ortert-butoxy group.

The C₁-C₄-alkanoyl group can be, for example, a formyl-, acetyl-,propanoyl-, butanoyl- or iso-butanoyl group.

The unbranched C₁-C₄-alkanoyloxy-C₁-C₄-alkylene group can be analkanoyloxymethyl-(AlkCOOCH₂—), 2-alkanoyloxyethyl-(AlkCOOCH₂CH₂—),1-alkanoyloxyethyl-[CH₃CH(OCOAlk)—],3-alkanoyloxypropyl-(AlkCOOCH₂CH₂CH₂—),2-alkanoyloxypropyl-[CH₃CH(OCOAlk)CH₂CH₂—],1-alkanoyloxypropyl-[CH₃CH₂CH(OCOAlk)—],4-alkanoyloxybutyl-(AlkCOOCH₂CH₂CH₂CH₂—),3-alkanoyloxybutyl-[CH₃CH(OCOAlk)CH₂CH₂—],2-alkanoyloxybutyl-[CH₃CH₂CH(OCOAlk)CH₂—] or 1-alkanoyloxybutyl[CH₃CH₂CH₂CH(OCOAlk)-] group.

The branched C₁-C₄-alkanoyloxy-C₃-C₅-alkyl group can be a1-alkanoyloxy-1-methylethyl-[(CH₃)₂C(OCOAlk)—],2-alkanoyloxy-1-methylethyl-[Alk-COOCH₂CH(CH₃)—],1-alkanoyloxy-1-methylpropyl-[CH₃CH₂C(CH₃)(OCOAlk)—],2-alkanoyloxy-1-methylpropyl-[CH₃CH(OCOAlk)CH(CH₃)—],3-alkanoyloxy-1-methylpropyl-[AlkCOOCH₂CH₂CH(CH₃)—],1-(alkanoyloxymethyl)propyl-[CH₃CH₂C(CH₂OCOAlk)—],1-alkanoyloxy-2-methylpropyl-[(CH₃)₂CHCH(OCOAlk)—],2-alkanoyloxy-2-methylpropyl-[CH₃C(OCOAlk)(CH₃)CH₂—],3-alkanoyloxy-2-methylpropyl-[AlkCOOCH₂CH(CH₃)CH₂—],1-(alkanoyloxymethyl)butyl-[CH₃CH₂CH₂CH(CH₂OCOAlk)-],1-alkanoyloxy-1-methylbutyl-[CH₃CH₂CH₂C(CH₃)(OCOAlk)-],2-alkanoyloxy-1-methylbutyl-[CH₃CH₂CH(OCOAlk)CH(CH₃)—],3-alkanoyloxy-1-methylbutyl-[CH₃CH(OCOAlk)CH₂CH(CH₃)—],4-alkanoyloxy-1-methylbutyl-[Alk-COOCH₂CH₂CH₂CH(CH₃)—],3-alkanoyloxy-1-ethylpropyl-[Alk-COOCH₂CH₂CH(CH₂CH₃)—],2-alkanoyloxy-1-ethylpropyl-[CH₃CH(OCOAlk)CH(CH₂CH₃)—],1-alkanoyloxy-1-ethylpropyl-[CH₃CH₂C(CH₂CH₃)(OCOAlk)-],1-alkanoyloxy-3-methylbutyl-[CH₃CH(CH₃)CH₂CH(OCOAlk)-],2-alkanoyloxy-3-methylbutyl-[(CH₃)₂CHCH(OCOAlk)CH₂—],3-alkanoyloxy-3-methylbutyl-[CH₃C(CH₃)(OCOAlk)CH₂CH₂—],4-alkanoyloxy-3-methylbutyl-[Alk-COOCH₂CH(CH₃)CH₂CH₂—],1-(alkanoyloxymethyl)-1-methylpropyl-[CH₃CH₂C(CH₃)(CH₂OCOAlk)-],2-alkanoyloxy-1,1-dimethylpropyl-[CH₃CH(OCOAlk)C(CH₃)₂—],23-alkanoyloxy-1,1-dimethylpropyl-[Alk-COOCH₂CH₂C(CH₃)₂—],1-(alkanoyloxymethyl)-2-methylpropyl-[(CH₃)₂CHCH(CH₂OCOAlk)-],1-alkanoyloxy-1,2-dimethylpropyl-[(CH₃)₂CHC(OCOAlk)(CH₃)—],2-alkanoyloxy-1,2-dimethylpropyl-[(CH₃)₂C(OCOAlk)CH(CH₃)—],3-alkanoyloxy-1,2-dimethylpropyl-[Alk-COOCH₂CH(CH₃)CH(CH₃)—],1-alkanoyloxy-2,2-dimethylpropyl-[(CH₃)₃CCH(OCOAlk)-],3-alkanoyloxy-2,2-dimethylpropyl-[Alk-COOCH₂C(CH₃)₂CH₂—],1-alkanoyloxy-2-methylbutyl-[CH₃CH₂CH(CH₃)CH(OCOAlk)-],2-alkanoyloxy-2-methylbutyl-[CH₃CH₂C(CH₃)(OCOAlk)CH₂—],3-alkanoyloxy-2-methylbutyl-[CH₃CH(OCOAlk)CH(CH₃)CH₂—],4-alkanoyloxy-2-methylbutyl-[Alk-COOCH₂CH₂CH(CH₃)CH₂—] or3-alkanoyloxy-2-ethylpropyl [Alk-COOCH₂CH(CH₂CH₃)CH₂—] group.

Leaving group X can be a halogen or a sulfonic ester group.

Halogen can be chlorine, bromine or iodine, whereby iodine is preferred.

The sulfonic ester group can be, for example, a mesylate,benzenesulfonate, tosylate, brosylate, triflate or nonaflate group.

The organic base is a tertiary amine or amide base, such as, forexample, triethylamine or ethyl diisopropylamine.

For the formation of pharmaceutically compatible salts of the compoundsof general formula I according to the invention, according to themethods that are known to one skilled in the art, i.a., hydrochloricacid, hydrobromic acid, sulfuric acid and phosphoric acid and nitricacid can be considered as inorganic acids; i.a., acetic acid, propionicacid, hexanoic acid, octanoic acid, decanoic acid, oleic acid, stearicacid, maleic acid, fumaric acid, succinic acid, benzoic acid, ascorbicacid, oxalic acid, salicylic acid, tartaric acid, citric acid, lacticacid, glycolic acid, malic acid, mandelic acid, cinnamic acid,glutaminic acid, and asparaginic acid can be considered as carboxylicacids; and i.a., methanesulfonic acid, ethanesulfonic acid,toluenesulfonic acid, benzenesulfonic acid as well asnaphthalenesulfonic acid can be considered as sulfonic acids.

Examples 1 to 58 of the compounds according to the invention that arementioned below under the Chapter “Production Process” are especiallypreferred.

Pharmacological Studies

The compounds according to the invention were tested in various models.The compounds of general formula I according to the invention aredistinguished in that in this case, these are compounds withanti-androgenic action that inhibit prostate tumor growth,simultaneously have a high, optionally oral bioavailability andoptionally destabilize the androgen receptor.

The in vitro tests on the influences on the activities of the androgenreceptor were performed as follows:

The following abbreviations are used:

-   -   Bicalutamide:        N-[4-Cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonyl]-2-hydroxy-2-methylpropanamide    -   R1881: Methyltrienolone,        17β-hydroxy-17α-methylestra-4,9,11-trien-3-one    -   CPA: Cyproterone acetate,        17-(acetyloxy)-6-chloro-1β,2β-dihydro-3′H-cyclopropa[1,2]pregna-1,4,6-triene-3,20-dione        Model 1: Inhibition of the Proliferation of LNCaP Cells

For the proliferation assay, 6000 LNCaP cells/well (Horoszewicz et al.Cancer Res. 1983, 43, 1809-1817) in a microtiter plate (96-well) in 50μl of RPMI1640 medium are grown with 5% CCS and cultivated as inModel 1. After 24 hours, the cells receive 50 μl of 2×-concentrated testsubstance, diluted in culture medium. The solvent concentration is 0.5%DMSO. After 4 days, the cells receive another 100 μl of 1×-concentratedtest substance, diluted in culture medium. After 7 to 8 days, theproliferation rate of the cells is determined by means of crystal violetassay (Gillies et al. Anal. Biochem. 1986, 159, 109-113). To determinethe antagonism, the substance treatment is performed in the presence of0.1 nmol of R1881 (1:1000 dilution of ethanolic solution). Control cellsreceive only 0.5% DMSO. For the agonism, the cells are treated only withtest substance (without R1881).

Table 1 shows the inhibitory action of test substances on theproliferation of the human androgen-dependent prostate cell line LNCaP.The inhibition of the cell proliferation is an important requirement forthe therapeutic use of the substances in the treatment of prostatecancer. The selected test substances according to the invention inhibitthe cell proliferation in the presence of 0.1 nmol of the syntheticandrogen R1881 with a considerably lower IC₅₀ (about 50×10⁻⁹ M), such asthe approved nonsteroidal anti-androgen bicalutamide (380×10⁻⁹ M). At asubstance concentration of 1 μmol, the proliferation compared to thecell growth in the presence of 0.1 nmol of R1881 is reduced by at least80%. Up to a tested concentration of 10 μmol, aproliferation-stimulating action was observed in none of the testsubstances.

It has been found, surprisingly enough, that the extent of theproliferation-inhibiting action ofN-[ω-[3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl]alkyl]derivatives is simultaneously dependent on chain substituents and thechain length. Especially for the pyrrolidine-substituted compounds thatare claimed here, the strongest antiproliferative action is observed inchain lengths between C₆ and C₉. Analogous compounds with shorter chainlengths n=4 (comparison 1) and n=5 (comparison 2) show a considerablyreduced antiproliferative activity. For the tested examples from U.S.Re. Pat No. 35956 [Examples 71 and 77] of the chain length n=2 and 4,little or no antiproliferative action could be detected. TABLE 1Inhibition of the Proliferation of LNCaP Cells by Test Substances. IC50% Inhibition Example Test Substance [10⁻⁹ M] at 1 μM BicalutamideN-[4-Cyano-3-(trifluoromethyl)phenyl]-3-[(4- 380 85fluorophenyl)sulfonyl]-2-hydroxy-2- methylpropanamide Comparison 14-[4,4-Dimethyl-5-oxo-3-[4-(pyrrolidin-1- 4300 20yl)butyl]-2-thioxoimidazolidin-1-yl]-2- (trifluoromethyl)benzonitrileComparison 2 4-[4,4-Dimethyl-5-oxo-3-[5-(pyrrolidin-1- 2100 38yl)pentyl]-2-thioxoimidazolidin-1-yl]-2- (trifluoromethyl)benzonitrileExample 71 4-[3-(2-Hydroxyethyl)-4,4-dimethyl-5-oxo-2- >10000 9 USRe35956 thioxoimidazolidin-1-yl]-2- (trifluoromethyl)benzonitrile Example77 4-[3-(4-Hydroxybutyl)-4,4-dimethyl-5-oxo-2- >10000 34 USRe 35956thioxoimidazolidin-1-yl]-2- (trifluoromethyl)benzonitrile  14-[4,4-Dimethyl-5-oxo-3-[8-(pyrrolidin-1- 45 98yl)octyl]-2-thioxoimidazolidin-1-yl]-2- (trifluoromethyl)benzonitrile  24-[4,4-Dimethyl-5-oxo-3-[8-(pyrrolidin-1- 41 100yl)octyl]-2-thioxoimidazolidin-1-yl]-2- (trifluoromethyl)benzonitrilehydrochloride  4 4-[4,4-Dimethyl-5-oxo-3-[7-(pyrrolidin-1- 45 98yl)heptyl]-2-thioxoimidazolidin-1-yl]-2- (trifluoromethyl)benzonitrile 6 4-[3-[6-[(2R)-2-(Hydroxymethyl)pyrrolidin-1- 55 102yl]hexyl]-4,4-dimethyl-5-oxo-2- thioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile  84-[3-[7-[(2R)-2-(Hydroxymethyl)pyrrolidin-1- 11 101yl]heptyl]-4,4-dimethyl-5-oxo-2- thioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile  94-[3-[7-[(2S)-2-(Hydroxymethyl)pyrrolidin-1- 26 92yl]heptyl]-4,4-dimethyl-5-oxo-2- thioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile 104-[3-[8-[(2R)-2-(Hydroxymethyl)pyrrolidin-1- <10 101yl]octyl]-4,4-dimethyl-5-oxo-2- thioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile 114-[3-[8-[(2S)-2-(Hydroxymethyl)pyrrolidin-1- 13 102yl]octyl]-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile 124-[3-[9-[(2R)-2-(Hydroxymethyl)pyrrolidin-1- 24 93yl]nonyl]-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile 134-[3-[9-[(2S)-2-(Hydroxymethyl)pyrrolidin-1- 16 88yl]nonyl]-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile 164-[3-[7-[(2R)-2-(Methoxymethyl)pyrrolidin-1- 18 98yl]heptyl]-4,4-dimethyl-5-oxo-2- thioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile 174-[3-[7-[(2S)-2-(Methoxymethyl)pyrrolidin-1- 32 99yl]heptyl]-4,4-dimethyl-5-oxo-2- thioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile 184-[3-[8-[(2R)-2-(Methoxymethyl)pyrrolidin-1- 11 103yl]octyl]-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile 194-[3-[8-[(2S)-2-(Methoxymethyl)pyrrolidin-1- 25 97yl]octyl]-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile 204-[3-[9-[(2R)-2-(Methoxymethyl)pyrrolidin-1- 29 101yl]nonyl]-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile 214-[3-[9-[(2S)-2-(Methoxymethyl)pyrrolidin-1- 47 94yl]nonyl]-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile 234-[3-[7-(3-Hydroxy-8-azabicyclo[3.2.1]oct-8- 48 79yl)heptyl]-4,4-dimethyl-5-oxo-2- thioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile 244-[3-[8-(3-Hydroxy-8-azabicyclo[3.2.1]oct-8- 13 102yl)octyl]-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile 274-[3-[7-[(R)-3-Hydroxypyrrolidin-1-yl]heptyl]-4,4- 57 95dimethyl-5-oxo-2-thioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile 284-[3-[8-[(R)-3-Hydroxypyrrolidin-1-yl]octyl]-4,4- 11 102dimethyl-5-oxo-2-thioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile 294-[3-[9-[(R)-3-Hydroxypyrrolidin-1-yl]nonyl]-4,4- 35 99dimethyl-5-oxo-2-thioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile 314-[3-[7-[(S)-3-Hydroxypyrrolidin-1-yl]heptyl]-4,4- 20 104dimethyl-5-oxo-2-thioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile 324-[3-[8-[(S)-3-Hydroxypyrrolidin-1-yl]octyl]-4,4- 12 101dimethyl-5-oxo-2-thioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile 354-[4,4-Dimethyl-3-[7-(2-methylpyrrolidin-1- 30 92yl)heptyl]-5-oxo-2-thioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile 364-[4,4-Dimethyl-3-[8-(2-methylpyrrolidin-1- 15 96yl)octyl]-5-oxo-2-thioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile 374-[3-[8-[(2R,5S)-rel-2,5-Dimethylpyrrolidin-1- 11 99yl]octyl]-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile 39 4-[3-[7-[(2S)-2-(1-Hydroxy-1-41 108 methylethyl)pyrrolidin-1-yl]heptyl]-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl]-2- (trifluoromethyl)benzonitrile 404-[3-[8-[(2S)-2-(1-Hydroxy-1- 11 118methylethyl)pyrrolidin-1-yl]octyl]-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl]-2- (trifluoromethyl)benzonitrile 414-[3-[9-[(2S)-2-(1-Hydroxy-1- 48 89methylethyl)pyrrolidin-1-yl]nonyl]-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl]-2- (trifluoromethyl)benzonitrile 434-[3-[7-[(2R)-2-(1-Hydroxy-1- 26 113methylethyl)pyrrolidin-1-yl]heptyl]-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl]-2- (trifluoromethyl)benzonitrile 444-[3-[8-[(2R)-2-(1-Hydroxy-1- 11 115methylethyl)pyrrolidin-1-yl]octyl]-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl]-2- (trifluoromethyl)benzonitrile 474-[3-[8-[(2S)-2-(1-Hydroxy-1- 27 99ethylpropyl)pyrrolidin-1-yl]octyl]-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl]-2- (trifluoromethyl)benzonitrile 49(S)-1-[6-[3-[4-Cyano-3-(trifluoromethyl)phenyl]- 32 1105,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl]hexyl]pyrrolidine-4-carboxamide 50(S)-1-[7-[3-[4-Cyano-3-(trifluoromethyl)phenyl]- 15 1105,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl]heptyl]pyrrolidine-4-carboxamide 51(S)-1-[8-[3-[4-Cyano-3-(trifluoromethyl)phenyl]- 20 975,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl]octyl]pyrrolidine-4-carboxamide 52(R)-1-[6-[3-[4-Cyano-3-(trifluoromethyl)phenyl]- 12 1005,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl]hexyl]pyrrolidine-4-carboxamide 53(R)-1-[7-[3-[4-Cyano-3-(trifluoromethyl)phenyl]- 49 975,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl]heptyl]pyrrolidine-4-carboxamide 54(R)-1-[8-[3-[4-Cyano-3-(trifluoromethyl)phenyl]- 64 935,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl]octyl]pyrrolidine-4-carboxamideModel 2: Anti-Androgenic Action of Selective Test Substances on theGrowth of the Accessory Reproductive Glands of Mice

The function and the size of accessory reproductive glands (prostate andseminal vesicles) depend on androgens. In castrated animals, a growth ofthese organs is induced by the administration of androgen. Simultaneoustreatment with anti-androgens inhibits this growth in a dose-dependentmanner.

For the examination of test substances, the mice were castrated. On thesame day, treatment with testosterone propionate (0.03 mg/mouse) and thetest substances (1× daily 10 or 30 mg/kg p.o. in benzyl benzoate-castoroil or ethanol/peanut oil (10:90)) was formulated. The treatment wascarried out over 7 days and at the end of the test, the weights of theseminal vesicles and prostate were determined. The inhibition of theseminal vesicle growth, in percent, was calculated in reference to thecontrol groups (with and without testosterone). As a referencesubstance, cyproterone acetate (30 mg/kg s.c. and p.o.) was used.

The results are shown in Table 2.

The tested compounds according to the invention show at least as good ananti-androgenic action on the seminal vesicles of the mouse as thecomparison substances CPA and bicalutamide. TABLE 2 Action of SelectiveTest Substances on the Testosterone-Stimulated Growth of the SeminalVesicles. % Inhibition of MSB Dose Example Test Substance Growth [mg/kg] 1 4-[4,4-Dimethyl-5-oxo-3-[8-(pyrrolidin-1-yl)octyl]- 99 30 p.o.2-thioxoimidazolidin-1-yl]-2- 82 10 p.o. (trifluoromethyl)benzonitrile 2 4-[4,4-Dimethyl-5-oxo-3-[8-(pyrrolidin-1- 95 30 p.o.yl)octyl]-2-thioxoimidazolidin-1-yl]-2- (trifluoromethyl)benzonitrilehydrochloride 10 4-[3-[8-[(2R)-2-(Hydroxymethyl)pyrrolidin-1- 87 10 p.o.yl]octyl]-4,4-dimethyl-5-oxo-2- thioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile 114-[3-[8-[(2S)-2-(Hydroxymethyl)pyrrolidin-1- 95 30 p.o.yl]octyl]-4,4-dimethyl-5-oxo-2- thioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile CPA17-(Acetyloxy)-6-chloro-1β,2β-dihydro-3′H- 85 30 s.c.cyclopropa[1,2]pregna-1,4,6-triene-3,20-dione BicalutamideN-[4-Cyano-3-(trifluoromethyl)phenyl]-3-[(4- 86 30 s.c.fluorophenyl)sulfonyl]-2-hydroxy-2- 82 30 p.o. methylpropanamideModel 3: Anti-Androgenic Action of a Selective Test Substance on theGrowth of Human Prostate Cancer Xenografts In Vivo

In this invention, the action of Example 1 according to the invention:4-[4,4-dimethyl-5-oxo-3-[8-(pyrrolidin-1-yl)octyl]-2-thioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile,11:4-[3-[8-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]octyl]-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrileand 23:4-[3-[7-(3-hydroxy-8-azabicyclo[3.2.1]oct-8-yl)heptyl]-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrileon the tumor growth in vivo was studied by means of mouse-xenograftmodels, in which the compounds according to the invention wereadministered 1× daily.

The CWR22 tumor model [M. A. Wainstein, F. He, D. Robinson, H. J. Kung,S. Schwartz, J. M. Giaconia, N. L. Edgehouse, T. P. Pretlow, D. R.Bodner, E. D. Kursh, Cancer Res. 1994, 1; 54(23), 6049-52] is ahormone-dependent human prostate cancer model. The tumor model wasestablished in immunodeficient hairless mice and further propagated by“serial passaging” of prostate cancer tissue, which was removed duringan OP. The androgen-dependent LNCaP prostate cancer model was alsoestablished by a patient tumor. This tumor model grows both in cellculture and as a xenotransplant in immunodeficient mice (Culig, HoffmannBrit. J Cancer, 1999, 242-251). For therapy tests, 6-week-old malehairless mice (NMRI-Maus, M&B, Bomholdtgard, Denmark) were supplementedwith testosterone pellets (12.5 mg, 90-day release, IRA, Sarasota,Fla.). In the animals, either LNCaP cells (1.5×10⁶ cells ) or smallCWR22 tumor fragments (2×2 mm) were implanted subcutaneously in the leftside. After the tumors reached a size of 20-25 mm², treatment was begunwith the invention substance. [M. A. Wainstein, F. He, D. Robinson, H.J. Kung, S. Schwartz, J. M. Giaconia, N. L. Edgehouse, T. P. Pretlow, D.R. Bodner, E. D. Kursh, Cancer Res. 1994, 1; 54(23), 6049-52].

The results are shown in FIGS. 1-4.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 illustrates results for growth inhibition of LNCaP prostatecancers by substance according to Example 1,

FIG. 2 illustrates results for growth inhibition of CWR22 prostatecancers by substance according to Example 1,

FIG. 3 illustrates results for growth inhibition of CWR22 prostatecancers by substance according to Example 11, and

FIG. 4 illustrates results for growth inhibition of CWR22 prostatecancers by substance according to Example 23.

FIG. 1. Growth inhibition of LNCaP prostate cancers by substanceaccording to Example 1. The treatment was carried out 1× daily p.o. with10 mg/kg. For comparison, bicalutamide as a reference substance wasadministered 1× daily at 30 mg/kg.

Key to FIG. 1:

-   Kontrolle=Control-   Kastr.=Castr.-   Bicalutamid=Bicalutamide-   Beispiel=Example    FIG. 2. Growth inhibition of CWR22 prostate cancers by substance    according to Example 1. The treatment was carried out 1× daily p.o.    with 30 mg/kg. For comparison, bicalutamide as a reference substance    was administered 1× daily at 30 mg/kg.    Key to FIG. 2:-   Kontrolle=Control-   Kastr.=Castr.-   Bicalutamid=Bicalutamide-   Substanz=Substance

While the tumor grows quickly in the untreated control animals,treatment with the compounds according to the invention results in aconsiderable growth inhibition of the prostate tumors, which is morestrongly pronounced than in the animals that are treated withbicalutamide. Both in the LNCaP tumor and in the CWR22 tumor, thisgrowth inhibition is comparable to the effects of castration (FIGS.1-2).

FIG. 3. Growth inhibition of CWR22 prostate cancers by substanceaccording to Example 11. The treatment was carried out 1× daily p.o.with 60 mg/kg. For comparison, bicalutamide as a reference substance wasadministered 1× daily at 60 mg/kg.

Key to FIG. 3:

-   Kontrolle=Control-   Kastr.=Castr.-   Bicalutamid=Bicalutamide-   Substanz=Substance

While the tumor grows quickly in the untreated control animals,treatment with the compounds according to the invention results in asignificant growth inhibition of the prostate tumors. In thisexperiment, the growth inhibition of the CWR22-prostate cancer iscomparable to the effects of castration (FIG. 3).

FIG. 4. Growth inhibition of CWR22 prostate cancers by substanceaccording to Example 23. The treatment was carried out 1× daily p.o.with 60 mg/kg. For comparison, bicalutamide as a reference substance wasadministered 1× daily at 60 mg/kg.

Key to FIG. 4:

-   Kontrolle=Control-   Kastr.=Castr.-   Bicalutamid=Bicalutamide-   Substanz=Substance

While the tumor grows quickly in the untreated control animals,treatment with the compounds according to the invention results in asignificant growth inhibition of the prostate tumors. In thisexperiment, the growth inhibition of the CR22-prostate cancer iscomparable to the effects of castration and superior to the comparisonsubstance bicalutamide (FIG. 4).

In this invention, the action of the compounds according to theinvention on tumor growth in vivo was studied by means of two differentmouse-xenograft models, in which the compounds according to theinvention were orally administered 1× daily over the entire treatmentperiod. In comparison to the untreated control animals, an inhibition ofthe tumor growth resulted. Retardation of the tumor growth was shown assignificant in castrated mice. The treatment was well tolerated.

In both models (CWR22; LNCaP), the inhibition of the tumor growth by thecompounds according to the invention is superior to the treatment withthe anti-androgen bicalutamide.

Model 4: Pharmacokinetics in Rats After Intravenous and PeroralAdministration

The pharmacokinetic properties of the compounds according to theinvention were studied in Examples 1:4-[4,4-dimethyl-5-oxo-3-[8-(pyrrolidin-1-yl)octyl]-2-thioxoimidazol-1-yl]-2-(trifluoromethyl)benzonitrileand 11:4-[3-[8-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]octyl]-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile.TABLE 3 Pharmacokinetic Properties of Selected Examples DeterminedParameters Example 1 Example 11 Distribution Volume V_(dss) [l/kg] 37 11Systemic Serum Clearance CL [ml/min/kg] 76 20 Half-Life i.v. T_(1/2) [h]5.6 5.7 Half-Life p.o. T_(1/2) [h] 6.1 8.0 Absorption T_(max) [h] 5 7Oral Bioavailability [%] 72 65

The determined pharmacokinetic data show very advantageouspharmacokinetic properties of the compounds according to the inventionin rats, which result in high oral bioavailability and a long half-life(>5h). The data indicate a high intestinal absorption and a relativelylow liver-first-pass-effect (increased metabolical stability).

Model 5: Destabilization of AR in LNCaP Cells by Test Substances

In a 25 cm² cell culture flask, 2×10⁶ LNCaP cells in 6 ml of RPMI 1640without phenol red are grown with 4 mmol of glutamine and 5% activatedcarbon-treated serum (CCS) and cultivated overnight at 37° C., 5% CO₂ ina humid atmosphere. On the next day, the cells are treated with the testsubstance at a concentration of 10 or 1 μmol, whereby the finalconcentration of the solvent is 0.5% DMSO. As a control, cells aretreated only with 0.5% DMSO. After an incubation time of 24 hours, themedium is changed with renewed administration of substance, and another24 hours of incubation. After 48 hours, the cells are washed with PBS,dissolved with PBS/20 mmol of EDTA, washed again with PBS-Ca²⁺/Mg²⁺ andthen frozen for at least 2 hours as a cell pellet at −80° C. Then, thecell pellet is resuspended in 200 μl of lysis buffer (50 mmol oftris/HCl, pH 7.5; 150 mmol of NaCl, 1.5 mmol of MgCl₂, 0.2% SDS, 10%glycerol, 1 mmol of DTT, 0.01× complete-EDTA protease inhibitors (Roche,Mannheim)) and treated with 10U benzonase (Merck, Darmstadt) for 10minutes at 4° C. After 5 mmol of EDTA is added, insoluble material ispelletized and 25 μg of the cell extract is separated in a 4-12%SDS-polyacrylamide gel (invitrogen). Then, the proteins are transferredto nitrocellulose (HyBondECL, Amersham) and incubated with monoclonalantibodies against the androgen receptor (AR441; Santa CruzBiotechnologies; 1:400 dilution) and actin (ICN, 1:5000-1:20000dilution). After incubation with the secondary antibody (anti mouseIgG-HRP, Amersham or -AP, invitrogen,), the Western Blot is developed bymeans of chemiluminescence (ECL, Amersham; Western Breeze, invitrogen),and the light signals are quantified with a Chemilmager™ (Kodak). Theamount of androgen receptor is calculated in a ratio to actin as apercentage of the DMSO control.

Table 4 shows the action of selected test substances at concentrationsof 10 or 1 μmol on the content of androgen receptor protein in the humanprostate cell line LNCaP. The data correspond to the proportion, inpercent, of the AR content of cells that were treated only with thesolvent DMSO (=control). The treatment of the cells with the cited testsubstances results, as in Example 56(4-[3-[7-[(2S)-4,4-dimethyl-5-oxo-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]heptyl]-2-thioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile)at a treatment concentration of 1 μmol, in a reduction of the AR contentto up to one-fourth of the control (24%). The comparison substancebi-calutamide does not influence the AR content, while the syntheticandrogen R1881 stabilizes the AR protein. The latter is known from theliterature (J. A. Kemppainen et. al. J. Biol. Chem. 1992, 267, 968-974).

By the reduction of the AR content, which presumably is carried out by adestabilization of the AR protein, the inhibitory action of theantihormones on cell proliferation is to be enhanced. TABLE 4 AR Content(%) in LNCaP Cells After Treatment with Selected Test Substances ARContent [%] at at Example Test Substance 10 μM 1 μM  14-[4,4-Dimethyl-5-oxo-3-[8-(pyrrolidin-1-yl)octyl]-2- 63thioxoimidazolidin-1-yl]-2-(trifluoromethyl)- benzonitrile  24-[4,4-Dimethyl-5-oxo-3-[8-(pyrrolidin-1-yl)octyl]-2- 50thioxoimidazolidin-1-yl]-2-(trifluoromethyl)- benzonitrile hydrochloride 9 4-[3-[7-[(2S)-2-(Hydroxymethyl)pyrrolidin-1- 63yl]heptyl]-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile 114-[3-[8-[(2S)-2-(Hydroxymethyl)pyrrolidin-1- 50yl]octyl]-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile 374-[3-[8-[(2R,5S)-rel-2,5-Dimethylpyrrolidin-1- 57yl]octyl]-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile 404-[3-[8-[(2S)-2-(1-Hydroxy-1-methylethyl)pyrrolidin- 401-yl]octyl]-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile 52(R)-1-[6-[3-[4-Cyano-3-(trifluoromethyl)phenyl]-5,5- 36 74dimethyl-4-oxo-2-thioxoimidazolidin-1-yl]hexyl]pyrrolidine-4-carboxamide 564-[3-[7-[(2S)-4,4-Dimethyl-5-oxo-2-(pyrrolidin-1- 24ylmethyl)pyrrolidin-1-yl]heptyl]-2-thioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile Comparison4-[3-(2-Hydroxyethyl)-4,4-dimethyl-5-oxo-2- 191 164 US Re. 35956thioxoimidazolidin-1-yl]-2-(trifluoromethyl)- Example 71 benzonitrileComparison 4-[3-(4-Hydroxybutyl)-4,4-dimethyl-5-oxo-2- 180 230 US Re.35956 thioxoimidazolidin-1-yl]-2-(trifluoromethyl)- Example 77benzonitrile Bicalutamide N-[4-Cyano-3-(trifluoromethyl)phenyl]-3-[(4-100 fluorophenyl)sulfonyl]-2-hydroxy-2- methylpropanamide R1881 (10 nM)17β-Hydroxy-17α-methylestra-4,9,11-trien-3-one 250

The compounds according to the invention are suitable for an extendedeffective treatment or prophylaxis of androgen-dependent diseases of thehuman or animal body. The compounds according to the invention aresuitable especially for the treatment or prophylaxis ofandrogen-dependent proliferative diseases, in particular prostatecancers and benign prostate hyperplasia (BHP).

This invention comprises pharmaceutical preparations that contain one ormore compounds of general formula I or their pharmaceutically compatiblesalts, optionally together with pharmaceutically compatible adjuvantsand/or vehicles, as well as the use of compounds of general formula Ifor the production of a pharmaceutical agent for treatment orprophylaxis of diseases of the human or animal body, which can beinfluenced by the inhibition of the androgen receptor.

In this sense, the compounds of general formula I according to theinvention as well as pharmaceutical preparations that contain the lattercan also be used for prophylaxis and/or therapy of otherandrogen-dependent images of disease or symptoms, which have anon-proliferative nature (e.g., androgenetic alopecia, hirsutism orandrogen-dependent acne).

Dosage

In general, satisfactory results can be expected when the daily dosescomprise a range of 5 μg to 50 mg of the compound according to theinvention per kg of body weight. In the case of larger mammals, forexample humans, a recommended daily dose is in the range of 10 μg to 30mg per kg of body weight. Suitable dosages for the compounds accordingto the invention are from 0.005 to 50 mg per day per kg of body weight,depending on age and constitution of the patient, whereby the necessarydaily dose can be administered one or more times.

The formulation of the pharmaceutical preparations based on the newcompounds is carried out in a way that is known in the art by the activeingredient being administered with the vehicles, fillers, substancesthat influence decomposition, binding agents, moisturizers, lubricants,absorbents, diluents, flavoring correctives, coloring agents, etc., thatare commonly used in galenicals and being converted into the desiredform of administration. In this case, reference is made to Remington'sPharmaceutical Science, 15^(th) ed. Mack Publishing Company, EastPennsylvania (1980).

For oral administration, in particular tablets, coated tablets,capsules, pills, powders, granulates, pastilles, suspensions, emulsionsor solutions are suitable. For parenteral administration, injection andinfusion preparations are possible. For intraarticulate injection,correspondingly prepared crystal suspensions can be used. For theintramuscular injection, aqueous and oily injection solutions orsuspensions, and corresponding depot preparations can be used. Forrectal administration, new compounds in the form of suppositories,capsules, solutions (e.g., in the form of enemas), and ointments can beused both for systemic and for local therapy. For topical application,formulations in gels, ointments, fatty ointments, creams, pastes,powders, milk, and tinctures are possible. The dosage of the compoundsof general formula I should be 0.01% -20% in these preparations toachieve an adequate pharmacological action. The topical application canalso be carried out by means of a transdermal system, for example apatch.

This invention comprises pharmaceutical compositions that contain atleast one compound of general formula I or at least one of theirpharmaceutically compatible salts, optionally together withpharmaceutically compatible adjuvants and/or vehicles.

These pharmaceutical compositions and pharmaceutical agents can beprovided for oral, rectal, subcutaneous, transdermal, percutaneous,intravenous or intramuscular administration. In addition to the commonlyused vehicles and/or diluents, they contain at least one compound ofgeneral formula I.

The pharmaceutical agents according to this invention are produced witha suitable dosage in a known way with the commonly used solid or liquidvehicles or diluents and the commonly used pharmaceutical-technicaladjuvants according to the desired type of administration. The preferredpreparations consist of a form for dispensing that is suitable for oraladministration. Such forms for dispensing are, for example, tablets,film tablets, coated tablets, capsules, pills, powders, solutions orsuspensions or else depot forms. The pharmaceutical compositions thatcontain at least one of the compounds according to the invention arepreferably administered orally.

Parenteral preparations, such as injection solutions, can also beconsidered. In addition, for example, suppositories an also be mentionedas preparations.

Corresponding tablets can be obtained by, for example, mixing the activeingredient with known adjuvants, for example inert diluents such asdextrose, sugar, sorbitol, mannitol, polyvinyl pyrrolidone, explosivessuch as corn starch or alginic acid, binding agents such as starch orgelatin, lubricants such as magnesium stearate or talc and/or agents forachieving a depot effect such as carboxylpolymethylene, carboxylmethylcellulose, cellulose acetate phthalate or polyvinyl acetate. The tabletscan also consist of several layers.

Coated tablets accordingly can be produced by coating cores, which areproduced analogously to the tablets, with agents that are commonly usedin tablet coatings, for example polyvinyl pyrrolidone or shellac, gumarabic, talc, titanium oxide or sugar. In this case, the shell of thecoated tablet can also consist of several layers, whereby the adjuvantsthat are mentioned above in the tablets can be used. In addition,solutions or suspensions with the compounds of general formula Iaccording to the invention can contain taste-improving agetns such assaccharine, cyclamate or sugar, as well as, e.g., flavoring substancessuch as vanilla or orange extract.

In addition, they can contain suspending adjuvants such as sodiumcarboxymethyl cellulose or preservatives such as p-hydroxybenzoates.

The capsules that contain compounds of general formula I can beproduced, for example, by the compound(s) of general formula I beingmixed with an inert vehicle such as lactose or sorbitol and encapsulatedin gelatin capsules.

Suitable suppositories can be produced by, for example, mixing withvehicles that are provided for this purpose, such as neutral fats orpolyethylene glycol or derivatives thereof.

For therapy and/or prophylaxis of androgen-dependent proliferativediseases, such as, for example, prostate cancers or benign prostatehyperplasia, the compounds according to the invention can beadministered combined with one or more of the following activeingredients:

-   1) Gonadotropic hormone (GNRH) agonists-   2) 5α-Reductase inhibitors such as finasteride-   3) Cytostatic agents-   4) VEGF-Kinase inhibitors-   5) Antigestagens-   6) Antiestrogens-   7) Antisense oligonucleotides-   8) EGF Antibodies-   9) Estrogens

It is also possible, in the treatment of prostate cancer with thecompounds according to the invention, to combine their use with a methodof clinical radiology that is known in the art (Laverdiere, J. et al.,1997, Intl. J. of Rad. Onc. Biol. Phys., 37, 247-252; Bolla, M. et al.,1997, New Engl. J. Med., 337, 95-300.)

The compounds of general formula I according to the invention can beproduced as described below.

This invention is explained in more detail based on the subsequentexamples without being limited thereto.

Synthesis Scheme

Thiohydantoin derivatives of chain lengths n=6 to 9 can be producedaccording to the following scheme:

Production Processes EXAMPLE 14-[4,4-Dimethyl-5-oxo-3-[8-(pyrrolidin-1-yl)octyl]-2-thioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile

1a) 8-Bromooctan-1-ol

25 g of octane-1,8-diol was boiled in 250 ml of cyclohexane with 22.6 mlof 47% aqueous hydrobromic acid for six hours in a water separator. Thereaction mixture was then poured onto saturated aqueous sodiumbicarbonate solution and extracted with ethyl acetate. The organic phasewas washed with saturated, aqueous sodium chloride solution, dried onsodium sulfate, filtered and concentrated by evaporation in a vacuum.Column chromatography on silica gel with a mixture that consists ofhexane/ethyl acetate yielded 21.6 g of the title compound as a yellowishoil.

¹H-NMR (300 MHz, CDCl₃): δ [ppm]=3.64 t (J=6.8 Hz, 2H, CH₂OH); 3.41 t(J=6.8 Hz, 2H, CH₂Br); 1.85 tt (J=7.3 Hz/6.8 Hz, 2H, CH₂); 1.56 m (2H,CH₂); 1.49-1.27 m (8H, CH₂).

1b) 2-(8-Hydroxyoctyl)-1H-isoindole-1,3(2H)-dione

A solution of 15.12 g of phthalic acid imide in 480 ml ofN,N-dimethylformamide was mixed in portions at room temperature with5.04 g of 50% sodium hydride as a dispersion in mineral oil. Thereaction mixture was stirred for one hour at room temperature. Then, asolution of 20 g of the compound, produced under 1a), in 480 ml ofN,N-dimethylformamide was added in drops, and the reaction mixture wasstirred for three hours at room temperature. The mixture was then pouredonto saturated aqueous sodium bicarbonate solution and extracted withethyl acetate. The organic phase was washed with saturated aqueoussodium chloride solution, dried on sodium sulfate, filtered andconcentrated by evaporation in a vacuum. Column chromatography on silicagel with a mixture that consists of hexane/ethyl acetate yielded 23.0 gof the title compound as a colorless foam.

¹H-NMR (300 MHz, CDCl₃): δ [ppm]=7.84 m (2H, aryl); 7.71 m (2H, aryl);3.68 t (J=7 Hz, 2H, CH₂N); 3.62 t (J=6 Hz, 2H, CH₂OH); 1.67 m (2H, CH₂);1.56 m (2H, CH₂); 1.32 m (8H, CH₂).

1c) 8-Aminooctan-1-ol

15.2 ml of 80% aqueous hydrazinium hydroxide was added in drops to asolution of 23 g of the compound, produced under 1b), in 400 ml ofethanol. The reaction mixture was boiled for four hours. The whiteprecipitate was filtered off and rewashed with ethanol. The filtrate wasconcentrated by evaporation in a vacuum. The residue was taken up inethyl acetate and irradiated for 30 minutes in an ultrasound bath. Thewhite precipitate was in turn filtered off and rewashed with ethylacetate. The filtrate was concentrated by evaporation in a vacuum. 8.88g of the title compound was obtained.

¹H-NMR (300 MHz, CDCl₃): δ [ppm]=3.62 t (J=7 Hz, 2H, CH₂OH); 2.68 t (J=6Hz, 2H, CH₂NH₂); 1.56 m (2H, CH₂); 1.32 m (10H, CH₂).

1d)4-[4,4-Dimethyl-5-oxo-3-(8-hydroxyoctyl)-2-thioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile

While being cooled in an ice bath and under nitrogen atmosphere, 2.3 mlof thiophosgene was added in drops to a solution of 4.99 g of4-amino-2-(trifluoromethyl)benzonitrile in 30 ml ofN,N-dimethylformamide. The reaction mixture was stirred for one hour atroom temperature and then mixed with water. The aqueous phase wasextracted with ethyl acetate. The combined organic phases were washedwith saturated aqueous sodium chloride solution, dried on sodiumsulfate, filtered and concentrated by evaporation in a vacuum. The thusobtained crude isothiocyanate was combined with the cyanamine producedby two hours of stirring of 5.4 ml of acetone cyanohydrin with 4.29 g ofthe compound produced under 1 c) in the presence of 3 g of molecularsieve 3 Å at room temperature and boiled for one hour with 7.47 ml oftriethylamine in 134 ml of tetrahydrofuran. The crude iminothiohydantoinobtained after concentration by evaporation in a vacuum was stirred with26.8 ml of 4 molar aqueous hydrochloric acid in 134 ml of methanolovernight at room temperature. The reaction mixture was then poured ontosaturated aqueous sodium bicarbonate solution and extracted with ethylacetate. The organic phase was washed with saturated aqueous sodiumchloride solution, dried on sodium sulfate, filtered and concentrated byevaporation in a vacuum. Column chromatography on silica gel with amixture that consists of hexane/ethyl acetate yielded 8.1 g of the titlecompound as a colorless foam.

¹H-NMR (300 MHz, CDCl₃): δ [ppm]=7.94 d (J=8 Hz, 1H, aryl); 7.89 d(J=2.1 Hz, 1H, aryl); 7.77 dd (J=8 Hz/2.1 Hz, 1H, aryl); 3.67 m (2H,CH₂N); 3.65 t (J=6.5 Hz, 2H, CH₂OH); 1.83 m (2H, CH₂); 1.55 m (2H, CH₂);1.58 s (6H, CH₃); 1.37 m (8H, CH₂).

1e)8-[3-[4-Cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl]octyl4-methylbenzenesulfonate

8.1 g of the compound produced under 1d) was stirred for one hour atroom temperature with 21.0 g of p-toluenesulfonic acid chloride and 25.5ml of triethylamine in 92 ml of dichloromethane. The reaction mixturewas poured into saturated, aqueous sodium bicarbonate solution andextracted with dichloromethane. The organic phase was washed withsaturated, aqueous sodium chloride solution, dried on sodium sulfate,filtered and concentrated by evaporation in a vacuum. Columnchromatography on silica gel with a mixture that consists ofhexane/ethyl acetate yielded 9.21 g of the title compound as a colorlessfoam.

¹H-NMR (300 MHz, CDCl₃): δ [ppm]=7.94 d (J=8 Hz, 1H, aryl); 7.89 d(J=2.1 Hz, 1H, aryl); 7.78 d (J=8.2 Hz, 2H, aryl); 7.77 dd (J=8 Hz/2.1Hz, 1H, aryl); 7.34 d (J=8.2 Hz, 2H, aryl); 4.03 t (J=6.5 Hz, 2H, CH₂O);3.66 m (2H, CH₂N); 2.45 s (3H, CH₃); 1.81 m (2H, CH₂); 1.65 m (2H, CH₂);1.58 s (6H, CH₃); 1.33 m (8H, CH₂).

1f)4-[4,4-Dimethyl-5-oxo-3-(8-iodooctyl)-2-thioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile

9.21 g of the compound produced under 1e) was boiled for one hour with9.3 g of sodium iodide in 150 ml of acetone. The reaction mixture wasfiltered at room temperature and concentrated by evaporation in avacuum. Column chromatography on silica gel with a mixture that consistsof hexane/ethyl acetate yielded 8.55 g of the title compound as ayellowish foam.

¹H-NMR (300 MHz, CDCl₃): δ [ppm]=7.95 d (J=8 Hz, 1H, aryl); 7.89 d(J=2.1 Hz, 1H, aryl); 7.77 dd (J=8 Hz/2.1 Hz, 1H, aryl); 3.67 m (2H,CH₂N); 3.20 t (J=7 Hz, 2H, CH₂I); 1.82 m (2H, CH₂); 1.80 m (2H, CH₂);1.58 s (6H, CH₃); 1.37 m (8H, CH₂).

1g)4-[4,4-Dimethyl-5-oxo-3-[8-(pyrrolidin-1-yl)octyl]-2-thioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile

200 mg of the compound produced under 1f) was boiled for four hours with60 μl of pyrrolidine and 101μl of triethylamine in 5 ml oftetrahydrofuran. The reaction mixture was concentrated by evaporation ina vacuum. Column chromatography on silica gel with a mixture thatconsists of hexane/ethyl acetate yielded 130 mg of the title compound asa colorless oil.

¹H-NMR (300 MHz, CDCl₃): δ [ppm]=7.94 d (J=8 Hz, 1H, aryl); 7.89 d(J=2.1 Hz, 1H, aryl); 7.77 dd (J=8 Hz / 2.1 Hz, 1H, aryl); 3.67 m (2H,CH₂N); 2.64 m (4H, CH₂N); 2.53 m (2H, CH₂N); 1.85 m (4H, CH₂); 1.82 m(2H, CH₂); 1.59 m (2H, CH₂); 1.58 s (6H, CH₃); 1.36 m (8H, CH₂).

EXAMPLE 24-[4,4-Dimethyl-5-oxo-3-[8-(pyrrolidin-1-yl)octyl]-2-thioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrilehydrochloride

20 mg of the compound, produced under 1 g), was dissolved in 1 ml oftetrahydrofuran and stirred for one hour at room temperature with 67 μlof a 1.2 molar solution of hydrochloric acid in diethyl ether. Thereaction mixture was concentrated by evaporation in a vacuum. 21 mg ofthe title compound was obtained.

¹H-NMR (300 MHz, CDCl₃): δ [ppm]=7.95 d (J=8 Hz, 1H, aryl); 7.89 d(J=2.1 Hz, 1H, aryl); 7.78 dd (J=8 Hz/2.1 Hz, 1H, aryl); 3.79 m (2H,CH₂N); 3.67 m (2H, CH₂N); 3.00 m (2H, CH₂N); 2.75 m (2H, CH₂N); 2.23 m(2H, CH₂); 2.06 (2H, CH₂); 1.90 m (2H, CH₂); 1.82 m (2H, CH₂); 1.59 s(6H, CH₃); 1.38 m (8H, CH₂).

EXAMPLE 34-[4,4-Dimethyl-5-oxo-3-[6-(pyrrolidin-1-yl)hexyl]-2-thioxoimidazolidin-1-yl]-2-(trifluoromethvl)benzonitrile

3a)4-[3-(6-Iodohexyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile

The production of the title compound was carried out analogously to theprocess described in Examples 1d) to 1f). 6-Aminohexan-1-ol was used asa chain component.

H-NMR (300 MHz, CDCl₃): δ [ppm]=7.95 d (J=8 Hz, 1H, aryl); 7.89 d (J=2.1Hz, 1H, aryl); 7.77 dd (J=8 Hz/2.1 Hz, 1H, aryl); 3.68 m (2H, CH₂N);3.21 t (J=6.8 Hz, 2H, CH₂I); 1.86 m (2H, CH₂); 1.83 m (2H, CH₂); 1.59 s(6H, CH₃); 1.46 m (4H, CH₂).

3b)4-[4,4-Dimethyl-5-oxo-3-[6-(pyrrolidin-1-yl)hexyl]-2-thioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile

20 mg of the compound, produced under 3a), was boiled for four hourswith 6.3 μl of pyrrolidine and 10.6 μl of triethylamine in 1 ml oftetrahydrofuran. The reaction mixture was concentrated by evaporation ina vacuum. Column chromatography on silica gel with a mixture thatconsists of hexane/ethyl acetate yielded 15 mg of the title compound asa colorless oil.

¹H-NMR (300 MHz, CDCl₃): δ [ppm]=7.95 d (J=8 Hz, 1H, aryl); 7.89 d(J=2.1 Hz, 1H, aryl); 7.77 dd (J=8 Hz/2.1 Hz, 1H, aryl); 3.68 m (2H,CH₂N); 2.75 m (4H, CH₂N); 2.64 m (2H, CH₂N); 1.90 m (4H, CH₂); 1.84 m(2H, CH₂); 1.68 m (2H, CH₂); 1.59 s (6H, CH₃); 1.43 m (4H, CH₂).

EXAMPLE 44-[4,4-Dimethyl-5-oxo-3-[7-(pyrrolidin-1-yl)heptyl]-2-thioxoimidazolidin-1-yl-2-(trifluoromethyl)benzonitrile

4a)4-[3-(7-Iodoheptyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile

The production of the title compound was carried out analogously to theprocess described in Examples 1a) to 1f). As a chain component,heptane-1,7-diol was used.

¹H-NMR (300 MHz, CDCl₃): δ [ppm]=7.95 d (J=8 Hz, 1H, aryl); 7.90 d(J=2.1 Hz, 1H, aryl); 7.78 dd (J=8 Hz /2.1 Hz, 1H, aryl); 3.67 m (2H,CH₂N); 3.20 t (J=7 Hz, 2H, CH₂I); 1.84 m (4H, CH₂); 1.59 s (6H, CH₃);1.41 m (6H, CH₂).

4b)4-[4,4-Dimethyl-5-oxo-3-[7-(pyrrolidin-1-yl)heptyl]-2-thioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile

13 mg of the compound produced under 4a) was boiled for four hours with4 μl of pyrrolidine and 6.7 μl of triethylamine in 1 ml oftetrahydrofuran. The reaction mixture was concentrated by evaporation ina vacuum. Column chromatography on silica gel with a mixture thatconsists of hexane/ethyl acetate yielded 7 mg of the title compound as acolorless oil.

¹H-NMR (300 MHz, CDCl₃): δ [ppm]=7.95 d (J=8 Hz, 1H, aryl); 7.89 d(J=2.1 Hz, 1H, aryl); 7.78 dd (J=8 Hz/2.1 Hz, 1H, aryl); 3.67 m (2H,CH₂N); 2.72 m (4H, CH₂N); 2.60 m (2H, CH₂N); 1.89 m (4H, CH₂); 1.83 m(2H, CH₂); 1.65 m (2H, CH₂); 1.58 s (6H, CH₃); 1.40 m (6H, CH₂).

EXAMPLE 54-[4,4-Dimethyl-5-oxo-3-[9-(pyrrolidin-1-yl)nonyl]-2-thioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile

5a)4-[3-(9-Iodononyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile

The production of the title compound was carried out analogously to theprocess described in Examples 1a) to 1f). Nonane-1,9-diol was used as achain component.

¹H-NMR (300 MHz, CDCl₃): δ [ppm]=7.95 d (J=8 Hz, 1H, aryl); 7.89 d(J=2.1 Hz, 1H, aryl); 7.77 dd (J=8 Hz/2.1 Hz, 1H, aryl); 3.67 m (2H,CH₂N); 3.19 t (J=7 Hz, 2H, CH₂I); 1.84 m (2H, CH₂); 1.82 m (2H, CH₂);1.58 s (6H, CH₃); 1.36 m (10H, CH₂).

5b)4-[4,4-Dimethyl-5-oxo-3-[9-(pyrrolidin-1-yl)nonyl]-2-thioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile

20 mg of the compound produced under 5a) was boiled for four hours with5.9 μl of pyrrolidine and 9.9 μl of triethylamine in 1 ml oftetrahydrofuran. The reaction mixture was concentrated by evaporation ina vacuum. Column chromatography on silica gel with a mixture thatconsists of hexane/ethyl acetate yielded 10 mg of the title compound asa colorless oil.

¹H-NMR (300 MHz, CDCl₃): δ [ppm]=7.95 d (J=8 Hz, 1H, aryl); 7.89 d(J=2.1 Hz, 1H, aryl); 7.77 dd (J=8 Hz/2.1 Hz, 1H, aryl); 3.66 m (2H,CH₂N); 2.47 m (4H, CH₂N); 2.40 m (2H, CH₂N); 1.77 m (4H, CH₂); 1.82 m(2H, CH₂); 1.58 s (6H, CH₃),1.51 m (2H, CH₂); 1.31 m (10H, CH₂).

Analogously to the production instructions, described in detail, inExamples 1 to 5, the following compounds were obtained: Product/Instructions ¹H-NMR (300 MHz, CDCl₃) Example Reagent analagous to δ[ppm] 6 4-[3-[6-[(2R)-2- 3 7.95 d(J=8Hz, 1H, aryl); 7.90 d(J=2.1Hz,(Hydroxymethyl)- 1H, aryl); 7.77 dd(J=8Hz/2.1Hz, pyrrolidin-1-yl]hexyl]-1H, aryl); 3.67 m(2H, CH₂N); 4,4-dimethyl-5-oxo-2- 3.62dd(J=10.5Hz/3.8Hz, 1H, CH₂OH); thioxoimidazolidin-1- 3.39dd(J=10.5Hz/2.1Hz, 1H, CH₂OH); yl]-2-(trifluoromethyl)- 3.19 m(1H,CH₂N); 2.73 dddbr(J=11.8Hz/ benzonitrile 7.6Hz/7.6Hz, 1H, CH₂N);(2R)-Pyrrolidinemethanol 2.58 m(1H, CH₂N); 2.25 m(2H, CH₂N); 1.96-1.67m(4H, CH₂); 1.84 m(2H, CH₂); 1.58 s(6H, CH₃); 1.54 m(2H, CH₂); 1.41m(4H, CH₂) 7 4-[3-[6-[(2S)-2- 3 7.95 d(J=8Hz, 1H, aryl); 7.90 d(J=2.1Hz,(Hydroxymethyl)- 1H, aryl); 7.77 dd(J=8Hz/2.1Hz, pyrrolidin-1-yl]hexyl]-1H, aryl); 3.67 m(2H, CH₂N); 4,4-dimethyl-5-oxo-2- 3.62dd(J=10.5Hz/3.8Hz, 1H, CH₂OH); thioxoimidazolidin-1- 3.39dd(J=10.5Hz/2.1Hz, 1H, CH₂OH); yl]-2-(trifluoromethyl)- 3.19 m(1H,CH₂N); 2.73 dddbr(J=11.8Hz/ benzonitrile 7.6Hz/7.6Hz, 1H, CH₂N);(2S)-Pyrrolidinemethanol 2.58 m(1H, CH₂N); 2.25 m(2H, CH₂N); 1.96-1.67m(4H, CH₂); 1.84 m(2H, CH₂); 1.58 s(6H, CH₃), 1.54 m(2H, CH₂); 1.41m(4H, CH₂) 8 4-[3-[7-[(2R)-2- 4 7.95 d(J=8Hz, 1H, aryl); 7.89 d(J=2.1Hz,(Hydroxymethyl)- 1H, aryl); 7.77 dd(J=8Hz/2.1Hz,pyrrolidin-1-yl]heptyl]- 1H, aryl); 3.67 m(2H, CH₂N);4,4-dimethyl-5-oxo-2- 3.62 dd(J=10.5Hz/3.8Hz, 1H, CH₂OH);thioxoimidazolidin-1- 3.39 dd(J=10.5Hz/2.5Hz, 1H, CH₂OH);yl]-2-(trifluoromethyl)- 3.18 m(1H, CH₂N); 2.71 dddbr(J=11.8Hz/benzonitrile 8Hz/8Hz, 1H, CH₂N); (2R)-Pyrrolidinemethanol 2.57 m(1H,CH₂N); 2.25 m(1H, CH₂N); 2.24 m(1H, CH₂N); 1.95-1.66 m(4H, CH₂); 1.80m(2H, CH₂); 1.58 s(6H, CH₃); 1.51 m(2H, CH₂); 1.39 m(6H, CH₂) 94-[3-[7-[(2S)-2- 4 7.95 d(J=8Hz, 1H, aryl); 7.89 d(J=2.1Hz,(Hydroxymethyl)- 1H, aryl); 7.77 dd(J=8Hz/2.1Hz,pyrrolidin-1-yl]heptyl]- 1H, aryl); 3.67 m(2H, CH₂N);4,4-dimethyl-5-oxo-2- 3.62 dd(J=10.5Hz/3.8Hz, 1H, CH₂OH);thioxo-imidazolidin-1- 3.39 dd(J=10.5Hz/2.5Hz, 1H, CH₂OH);yl]-2-(trifluoromethyl)- 3.18 m(1H, CH₂N); 2.71 dddbr(J=11.8Hz/benzonitrile 8Hz/8Hz, 1H, CH₂N); (2S)-Pyrrolidinemethanol 2.57 m(1H,CH₂N); 2.25 m(1H, CH₂N); 2.24 m(1H, CH₂N); 1.95-1.66 m(4H, CH₂); 1.80m(2H, CH₂); 1.58 s(6H, CH₃); 1.51 m(2H, CH₂); 1.39 m(6H, CH₂) 104-[3-[8-[(2R)-2- 1 7.95 d(J=8Hz, 1H, aryl); 7.89 d(J=2.1Hz,(Hydroxymethyl)- 1H, aryl); 7.78 dd(J=8Hz/2.1Hz, pyrrolidin-1-yl]octyl]-1H, aryl); 3.67 m(2H, CH₂N); 4,4-dimethyl-5-oxo-2- 3.63dd(J=10.5Hz/3.8Hz, 1H, CH₂OH); thioxoimidazolidin-1- 3.39dd(J=10.5Hz/2.5Hz, 1H, CH₂OH); yl]-2-(trifluoromethyl)- 3.18 m(1H,CH₂N); 2.71 dddbr(J=11.8Hz/ benzonitrile 8Hz/8Hz, 1H, CH₂N);(2R)-Pyrrolidinemethanol 2.58 m(1H, CH₂N); 2.25 m(2H, CH₂N); 1.96-1.67m(4H, CH₂); 1.82 m(2H, CH₂); 1.58 s(6H, CH₃); 1.50 m(2H, CH₂); 1.36m(8H, CH₂) 11 4-[3-[8-[(2S)-2- 1 7.95 d(J=8Hz, 1H, aryl); 7.89d(J=2.1Hz, (Hydroxymethyl)- 1H, aryl); 7.78 dd(J=8Hz/2.1Hz,pyrrolidin-1-yl]octyl]- 1H, aryl); 3.67 m(2H, CH₂N);4,4-dimethyl-5-oxo-2- 3.63 dd(J=10.5Hz/3.8Hz, 1H, CH₂OH);thioxoimidazolidin-1- 3.39 dd(J=10.5Hz/2.5Hz, 1H, CH₂OH);yl]-2-(trifluoromethyl)- 3.18 m(1H, CH₂N); 2.71 dddbr(J=11.8Hz/benzonitrile 8Hz/8Hz, 1H, CH₂N); (2S)-Pyrrolidinemethanol 2.58 m(1H,CH₂N); 2.25 m(2H, CH₂N); 1.96-1.67 m(4H, CH₂); 1.82 m(2H, CH₂); 1.58s(6H, CH₃); 1.50 m(2H, CH₂); 1.36 m(8H, CH₂) 12 4-[3-[9-[(2R)-2- 5 7.95d(J=8Hz, 1H, aryl); 7.90 d(J=2.1Hz, (Hydroxymethyl)- 1H, aryl); 7.77dd(J=8Hz/2.1Hz, pyrrolidin-1-yl]nonyl]- 1H, aryl); 3.67 m(2H, CH₂N);4,4-dimethyl-5-oxo-2- 3.62 dd(J=10.5Hz/3.8Hz, 1H, CH₂OH);thioxoimidazolidin-1- 3.38 dd(J=10.5Hz/2.5Hz, 1H, CH₂OH);yl]-2-(trifluoromethyl)- 3.17 m(1H, CH₂N); 2.70 dddbr(J=11.8Hz/benzonitrile 8.4Hz/8Hz, 1H, CH₂N); (2R)-Pyrrolidinemethanol 2.56 m(1H,CH₂N); 2.24 m(1H, CH₂N); 2.21 m(1H, CH₂N); 1.92-1.67 m(4H, CH₂); 1.82m(2H, CH₂); 1.58 s(6H, CH₃); 1.48 m(2H, CH₂); 1.31 m(10H, CH₂) 134-[3-[9-[(2S)-2- 5 7.95 d(J=8Hz, 1H, aryl); 7.90 d(J=2.1Hz,(Hydroxymethyl)- 1H, aryl); 7.77 dd(J=8Hz/2.1Hz, pyrrolidin-1-yl]nonyl]-1H, aryl); 3.67 m(2H, CH₂N); 4,4-dimethyl-5-oxo-2- 3.62dd(J=10.5Hz/3.8Hz, 1H, CH₂OH); thioxoimidazolidin-1- 3.38dd(J=10.5Hz/2.5Hz, 1H, CH₂OH); yl]-2-(trifluoromethyl)- 3.17 m(1H,CH₂N); 2.70 dddbr(J=11.8Hz/ benzonitrile 8.4Hz/8Hz, 1H, CH₂N);(2S)-Pyrrolidinemethanol 2.56 m(1H, CH₂N); 2.24 m(1H, CH₂N); 2.21 m(1H,CH₂N); 1.92-1.67 m(4H, CH₂); 1.82 m(2H, CH₂); 1.58 s(6H, CH₃); 1.48m(2H, CH₂); 1.31 m(10H, CH₂) 14 4-[3-[6-[(2R)-2- 3 7.95 d(J=8Hz, 1H,aryl); 7.89 d(J=2.1Hz, (Methoxymethyl)- 1H, aryl); 7.77 dd(J=8Hz/2.1Hz,pyrrolidin-1-yl]hexyl]- 1H, aryl); 3.67 m(2H, CH₂N);4,4-dimethyl-5-oxo-2- 3.42 dd(J=9.3Hz/5.1Hz, 1H, CH₂O);thioxoimidazolidin-1- 3.35 s(3H, CH₃O); 3.28 dd(J=9.3Hz/5.9Hz,yl]-2-(trifluoromethyl)- 1H, CH₂O); 3.16 m(1H, CH₂N); benzonitrile 2.85dddbr(J=11.8Hz/8.4Hz/8Hz, 1H, (2R)-2-(Methoxymethyl) CH₂N); 2.56 m(1H,CH₂N); pyrrolidine 2.26 dddbr(J=11.8Hz/7.6Hz/7.6Hz, 1H, CH₂N); 2.17m(1H, CH₂N); 1.92-1.67 m(4H, CH₂); 1.83 m(2H, CH₂); 1.57 s(6H, CH₃);1.54 m(2H, CH₂); 1.40 m(4H, CH₂) 15 4-[3-[6-[(2S)-2- 3 7.95 d(J=8Hz, 1H,aryl); 7.89 d(J=2.1Hz, (Methoxymethyl)- 1H, aryl); 7.77 dd(J=8Hz/2.1Hz,pyrrolidin-1-yl]hexyl]- 1H, aryl); 3.67 m(2H, CH₂N);4,4-dimethyl-5-oxo-2- 3.42 dd(J=9.3Hz/5.1Hz, 1H, CH₂O);thioxoimidazolidin-1- 3.35 s(3H, CH₃O); 3.28 dd(J=9.3Hz/5.9Hz,yl]-2-(trifluoromethyl)- 1H, CH₂O); 3.16 m(1H, CH₂N); benzonitrile 2.85dddbr(J=11.8Hz/8.4Hz/8Hz, 1H, (2S)-2-(Methoxymethyl) CH₂N); 2.56 m(1H,CH₂N); pyrrolidine 2.26 dddbr(J=11.8Hz/7.6Hz/7.6Hz, 1H, CH₂N); 2.17m(1H, CH₂N); 1.92-1.67 m(4H, CH₂); 1.83 m(2H, CH₂); 1.57 s(6H, CH₃);1.54 m(2H, CH₂); 1.40 m(4H, CH₂) 16 4-[3-[7-[(2R)-2- 4 7.95 d(J=8Hz, 1H,aryl); 7.89 d(J=2.1Hz, (Methoxymethyl)- 1H, aryl); 7.77 dd(J=8Hz/2.1Hz,pyrrolidin-1-yl]heptyl]- 1H, aryl); 3.66 m(2H, CH₂N);4,4-dimethyl-5-oxo-2- 3.42 dd(J=9.3Hz/5.1Hz, 1H, CH₂O);thioxoimidazolidin-1- 3.35 s(3H, CH₃O); 3.27 dd(J=9.3Hz/5.9Hz,yl]-2-(trifluoromethyl)- 1H, CH₂O); 3.14 m(1H, CH₂N); benzonitrile 2.83dddbr(J=11.8Hz/8.4Hz/8Hz, 1H, (2R)-2- CH₂N); 2.55 m(1H, CH₂N);(Methoxymethyl)- 2.24 dddbr(J=11.8Hz/7.6Hz/7.6Hz, 1H, pyrrolidine CH₂N);2.16 m(1H, CH₂N); 1.92-1.67 m(4H, CH₂); 1.83 m(2H, CH₂); 1.58 s(6H,CH₃); 1.51 m(2H, CH₂); 1.38 m(6H, CH₂) 17 4-[3-[7-[(2S)-2- 4 7.95d(J=8Hz, 1H, aryl); 7.89 d(J=2.1Hz, (Methoxymethyl)- 1H, aryl); 7.77dd(J=8Hz/2.1Hz, pyrrolidin-1-yl]heptyl]- 1H, aryl); 3.66 m(2H, CH₂N);4,4-dimethyl-5-oxo-2- 3.42 dd(J=9.3Hz/5.1Hz, 1H, CH₂O);thioxoimidazolidin-1- 3.35 s(3H, CH₃O); 3.27 dd(J=9.3Hz/5.9Hz,yl]-2-(trifluoromethyl)- 1H, CH₂O); 3.14 m(1H, CH₂N); benzonitrile 2.83dddbr(J=11.8Hz/8.4Hz/8Hz, 1H, (2S)-2-(Methoxymethyl) CH₂N); 2.55 m(1H,CH₂N); pyrrolidine 2.24 dddbr(J=11.8Hz/7.6Hz/7.6Hz, 1H, CH₂N); 2.16m(1H, CH₂N); 1.92-1.67 m(4H, CH₂); 1.83 m(2H, CH₂); 1.58 s(6H, CH₃);1.51 m(2H, CH₂); 1.38 m(6H, CH₂) 18 4-[3-[8-[(2R)-2- 1 7.94 d(J=8Hz, 1H,aryl); 7.89 d(J=2.1Hz, (Methoxymethyl)- 1H, aryl); 7.77 dd(J=8Hz/2.1Hz,pyrrolidin-1-yl]octyl]- 1H, aryl); 3.66 m(2H, CH₂N);4,4-dimethyl-5-oxo-2- 3.43 dd(J=9.3Hz/5.1Hz, 1H, CH₂O);thioxoimidazolidin-1- 3.35 s(3H, CH₃O); 3.27 dd(J=9.3Hz/5.9Hz,yl]-2-(trifluoromethyl)- 1H, CH₂O); 3.15 m(1H, CH₂N); benzonitrile 2.82dddbr(J=11.8Hz/8.4Hz/8Hz, 1H, (2R)-2-(Methoxymethyl) CH₂N); 2.56 m(1H,CH₂N); pyrrolidine 2.24 dddbr(J=11.8Hz/7.6Hz/7.6Hz, 1H, CH₂N); 2.17m(1H, CH₂N); 1.92-1.67 m(4H, CH₂); 1.82 m(2H, CH₂); 1.58 s(6H, CH₃);1.51 m(2H, CH₂); 1.36 m(8H, CH₂) 19 4-[3-[8-[(2S)-2- 1 7.94 d(J=8Hz, 1H,aryl); 7.89 d(J=2.1Hz, (Methoxymethyl)- 1H, aryl); 7.77 dd(J=8Hz/2.1Hz,pyrrolidin-1-yl]octyl]- 1H, aryl); 3.66 m(2H, CH₂N);4,4-dimethyl-5-oxo-2- 3.43 dd(J=9.3Hz/5.1Hz, 1H, CH₂O);thioxoimidazolidin-1- 3.35 s(3H, CH₃O); 3.27 dd(J=9.3Hz/5.9Hz,yl]-2-(trifluoromethyl)- 1H, CH₂O); 3.15 m(1H, CH₂N); benzonitrile 2.82dddbr(J=11.8Hz/8.4Hz/8Hz, 1H, (2S)-2-(Methoxymethyl) CH₂N); 2.56 m(1H,CH₂N); pyrrolidine 2.24 dddbr(J=11.8Hz/7.6Hz/7.6Hz, 1H, CH₂N); 2.17m(1H, CH₂N); 1.92-1.67 m(4H, CH₂); 1.82 m(2H, CH₂); 1.58 s(6H, CH₃);1.51m(2H, CH₂); 1.36 m(8H, CH₂) 20 4-[3-[9-[(2R)-2- 5 7.95 d(J=8Hz, 1H,aryl); 7.89 d(J=2.1Hz, (Methoxymethyl)- 1H, aryl); 7.77 dd(J=8Hz/2.1Hz,pyrrolidin-1-yl]nonyl]- 1H, aryl); 3.66 m(2H, CH₂N);4,4-dimethyl-5-oxo-2- 3.41 dd(J=9.3Hz/5.1Hz, 1H, CH₂O);thioxoimidazolidin-1- 3.35 s(3H, CH₃O); 3.27 dd(J=9.3Hz/5.9Hz,yl]-2-(trifluoromethyl)- 1H, CH₂O); 3.13 m(1H, CH₂N); benzonitrile 2.80dddbr(J=11.8Hz/8.4Hz/8Hz, 1H, (2R)-2-(Methoxymethyl) CH₂N); 2.53 m(1H,CH₂N); pyrrolidine 2.22 dddbr(J=11.8Hz/7.6Hz/7.6Hz, 1H, CH₂N); 2.15m(1H, CH₂N); 1.92-1.67 m(4H, CH₂); 1.83 m(2H, CH₂); 1.58 s(6H, CH₃);1.49 m(2H, CH₂); 1.31 m(10H, CH₂) 21 4-[3-[9-[(2S)-2- 5 7.95 d(J=8Hz,1H, aryl); 7.89 d(J=2.1Hz, (Methoxymethyl)- 1H, aryl); 7.77dd(J=8Hz/2.1Hz, pyrrolidin-1-yl]nonyl]- 1H, aryl); 3.66 m(2H, CH₂N);4-dimethyl-5-oxo-2- 3.41 dd(J=9.3Hz/5.1Hz, 1H, CH₂O);thioxoimidazolidin-1- 3.35 s(3H, CH₃O); 3.27 dd(J=9.3Hz/5.9Hz,yl]-2-(trifluoromethyl)- 1H, CH₂O); 3.13 m(1H, CH₂N); benzonitrile 2.80dddbr(J=11.8Hz/8.4Hz/8Hz, 1H, (2S)-2-(Methoxymethyl) CH₂N); 2.53 m(1H,CH₂N); pyrrolidine 2.22 dddbr(J=11.8Hz/7.6Hz/7.6Hz, 1H, CH₂N); 2.15m(1H, CH₂N); 1.92-1.67 m(4H, CH₂); 1.83 m(2H, CH₂); 1.58 s(6H, CH₃);1.49 m(2H, CH₂); 1.31 m(10H, CH₂) 22 4-[3-[6-(3-Hydroxy-8- 3 7.95d(J=8Hz, 1H, aryl); 7.90 d(J=2.1Hz, azabicyclo[3.2.1]oct-8- 1H, aryl);7.79 dd(J=8Hz/2.1Hz, yl)hexyl]-4,4-dimethyl- 1H, aryl); 4.04 m(1H,CHOH); 5-oxo-2-thioxoimidazolidin- 3.69 m(2H, CH₂N); 3.19 m(2H, CHN);1-yl]-2- 2.35 m(2H, CH₂N); 2.05 m(4H, CH₂); (trifluoromethyl)- 1.91m(2H, CH₂); 1.86 m(2H, CH₂); benzonitrile 1.62 m(2H, CH₂); 1.58 s(6H,CH₃); 8-Azabicyclo[3.2.1]- 1.53 m(2H, CH₂); 1.40 m(4H, CH₂) octan-3-ol23 4-[3-[7-(3-Hydroxy-8- 4 7.95 d(J=8Hz, 1H, aryl); 7.89 d(J=2.1Hz,azabicyclo[3.2.1]oct-8- 1H, aryl); 7.77 dd(J=8Hz/2.1Hz,yl)heptyl]-4,4-dimethyl- 1H, aryl); 4.05 m(1H, CHOH);5-oxo-2-thioxoimidazolidin- 3.66 m(2H, CH₂N); 3.19 m(2H, CHN); 1-yl]-2-2.33 m(2H, CH₂N); 2.07 m(4H, CH₂); (trifluoromethyl)- 1.92 m(2H, CH₂);1.82 m(2H, CH₂); benzonitrile 1.62 m(2H, CH₂); 1.58 s(6H, CH₃);8-Azabicyclo[3.2.1]- 1.49 m(2H, CH₂); 1.38 m(6H, CH₂) octan-3-ol 244-[3-[8-(3-Hydroxy-8- 1 7.95 d(J=8Hz, 1H, aryl); 7.89 d(J=2.1Hz,azabicyclo[3.2.1]oct-8- 1H, aryl); 7.78 dd(J=8Hz/2.1Hz,yl)octyl]-4,4-dimethyl-5- 1H, aryl); 4.05 m(1H, CHOH);oxo-2-thioxoimidazolidin- 3.66 m(2H, CH₂N); 3.19 m(2H, CHN); 1-yl]-2-2.33 m(2H, CH₂N); 2.07 m(4H, CH₂); trifluoromethyl)- 1.92 m(2H, CH₂);1.81 m(2H, CH₂); benzonitrile 1.62 m(2H, CH₂); 1.59 s(6H, CH₃);8-Azabicyclo[3.2.1]- 1.48 m(2H, CH₂); 1.38 m(8H, CH₂) octan-3-ol 254-[3-[9-(3-Hydroxy-8- 5 7.95 d(J=8Hz, 1H, aryl); 7.89 d(J=2.1Hz,azabicyclo[3.2.1]oct-8- 1H, aryl); 7.77 dd(J=8Hz/2.1Hz,yl)nonyl]-4,4-dimethyl- 1H, aryl); 4.04 m(1H, CHOH);5-oxo-2-thioxoimidazolidin- 3.66 m(2H, CH₂N); 3.19 m(2H, CHN); 1-yl]-2-2.33 m(2H, CH₂N); 2.08 m(4H, CH₂); (trifluoromethyl)- 1.91 m(2H, CH₂);1.82 m(2H, CH₂); benzonitrile 1.62 m(2H, CH₂); 1.58 s(6H, CH₃);8-Azabicyclo[3.2.1]- 1.48 m(2H, CH₂); 1.31 m(10H, CH₂) octan-3-ol 264-[3-[6-[(R)-3- 3 7.95 d(J=8Hz, 1H, aryl); 7.89 d(J=2.1Hz,Hydroxypyrrolidin-1- 1H, aryl); 7.77 dd(J=8Hz/2.1Hz,yl]hexyl]-4,4-dimethyl- 1H, aryl); 4.34 m(1H, CHOH);5-oxo-2-thioxoimidazolidin- 3.67 m(2H, CH₂N); 2.89 m(1H, CH₂N); 1-yl]-2-2.69 m(1H, CH₂N); 2.50 m(1H, CH₂N); (trifluoromethyl)- 2.46 m(2H, CH₂N);2.28 m(1H, benzonitrile CH₂N); 2.20 m(1H, CH₂); 1.83 m(2H,(R)-Pyrrolidin-3-ol CH₂); 1.74 m(1H, CH₂); 1.57 s(6H, CH₃); 1.56 m(2H,CH₂); 1.41 m(4H, CH₂) 27 4-[3-[7-[(R)-3- 4 7.95 d(J=8Hz, 1H, aryl); 7.89d(J=2.1Hz, Hydroxypyrrolidin-1- 1H, aryl); 7.77 dd(J=8Hz/2.1Hz,yl]heptyl]-4,4-dimethyl- 1H, aryl); 4.34 m(1H, CHOH);5-oxo-2-thioxoimidazolidin- 3.66 m(2H, CH₂N); 2.89 m(1H, CH₂N); 1-yl]-2-2.69 m(1H, CH₂N); 2.52 m(1H, CH₂N); (trifluoromethyl)- 2.45 m(2H, CH₂N);2.30 m(1H, benzonitrile CH₂N); 2.17 m(1H, CH₂); 1.83 m(2H,(R)-Pyrrolidin-3-ol CH₂); 1.74 m(1H, CH₂); 1.58 s(6H, CH₃); 1.52 m(2H,CH₂); 1.39 m(6H, CH₂) 28 4-[3-[8-[(R)-3- 1 7.95 d(J=8Hz, 1H, aryl); 7.89d(J=2.1Hz, Hydroxypyrrolidin-1- 1H, aryl); 7.77 dd(J=8Hz/2.1Hz,yl]octyl]-4,4-dimethyl-5- 1H, aryl); 4.34 m(1H, CHOH);oxo-2-thioxoimidazolidin- 3.66 m(2H, CH₂N); 2.89 m(1H, CH₂N); 1-yl]-2-2.70 m(1H, CH₂N); 2.53 m(1H, CH₂N); (trifluoromethyl)- 2.45 m(2H, CH₂N);2.30 m(1H, benzonitrile CH₂N); 2.19 m(1H, CH₂); 1.82 m(2H,(R)-Pyrrolidin-3-ol CH₂); 1.75 m(1H, CH₂); 1.58 s(6H, CH₃); 1.51 m(2H,CH₂); 1.35 m(8H, CH₂) 29 4-[3-[9-[(R)-3- 5 7.95 d(J=8Hz, 1H, aryl); 7.89d(J=2.1Hz, Hydroxypyrrolidin-1- 1H, aryl); 7.77 dd(J=8Hz/2.1Hz,yl]nonyl]-4,4-dimethyl- 1H, aryl); 4.32 m(1H, CHOH);5-oxo-2-thioxoimidazolidin- 3.66 m(2H, CH₂N); 2.87 m(1H, CH₂N); 1-yl]-2-2.66 m(1H, CH₂N); 2.48 m(1H, CH₂N); (trifluoromethyl)- 2.41 m(2H, CH₂N);2.25 m(1H, benzonitrile CH₂N); 2.17 m(1H, CH₂); 1.82 m(2H,(R)-Pyrrolidin-3-ol CH₂); 1.72 m(1H, CH₂); 1.58 s(6H, CH₃); 1.49 m(2H,CH₂); 1.31 m(10H, CH₂) 30 4-[3-[6-[(S)-3- 3 7.95 d(J=8Hz, 1H, aryl);7.89 d(J=2.1Hz, Hydroxypyrrolidin-1- 1H, aryl); 7.77 dd(J=8Hz/2.1Hz,yl]hexyl]-4,4-dimethyl- 1H, aryl); 4.37 m(1H, CHOH);5-oxo-2-thioxoimidazolidin- 3.67 m(2H, CH₂N); 2.94 m(1H, CH₂N); 1-yl]-2-2.75 m(1H, CH₂N); 2.59 m(1H, CH₂N); (trifluoromethyl)- 2.51 m(2H, CH₂N);2.37 m(1H, benzonitrile CH₂N); 2.21 m(1H, CH₂); 1.83 m(2H,(S)-Pyrrolidin-3-ol CH₂); 1.81 m(1H, CH₂); 1.58 s(6H, CH₃); 1.57 m(2H,CH₂); 1.42 m(4H, CH₂) 31 4-[3-[7-[(S)-3- 4 7.95 d(J=8Hz, 1H, aryl); 7.89d(J=2.1Hz, Hydroxypyrrolidin-1- 1H, aryl); 7.77 dd(J=8Hz/2.1Hz,yl]heptyl]-4,4-dimethyl- 1H, aryl); 4.37 m(1H, CHOH);5-oxo-2-thioxoimidazolidin- 3.66 m(2H, CH₂N); 2.95 m(1H, CH₂N); 1-yl]-2-2.75 m(1H, CH₂N); 2.61 m(1H, CH₂N); (trifluoromethyl)- 2.52 m(2H, CH₂N);2.40 m(1H, benzonitrile CH₂N); 2.21 m(1H, CH₂); 1.83 m(2H,(S)-Pyrrolidin-3-ol CH₂); 1.81 m(1H, CH₂); 1.58 s(6H, CH₃); 1.56 m(2H,CH₂); 1.39 m(6H, CH₂) 32 4-[3-[8-[(S)-3- 1 7.95 d(J=8Hz, 1H, aryl); 7.89d(J=2.1Hz, Hydroxypyrrolidin-1- 1H, aryl); 7.77 dd(J=8Hz/2.1Hz,yl]octyl]-4,4-dimethyl-5- 1H, aryl); 4.34 m(1H, CHOH);oxo-2-thioxoimidazolidin- 3.67 m(2H, CH₂N); 2.89 m(1H, CH₂N); 1-yl]-2-2.70 m(1H, CH₂N); 2.53 m(1H, CH₂N); (trifluoromethyl)- 2.45 m(2H, CH₂N);2.30 m(1H, benzonitrile CH₂N); 2.19 m(1H, CH₂); 1.82 m(2H,(S)-Pyrrolidin-3-ol CH₂); 1.75 m(1H, CH₂); 1.58 s(6H, CH₃); 1.51 m(2H,CH₂); 1.36 m(8H, CH₂) 33 4-[3-[9-[(S)-3- 5 7.95 d(J=8Hz, 1H, aryl); 7.89d(J=2.1Hz, Hydroxypyrrolidin-1- 1H, aryl); 7.77 dd(J=8Hz/2.1Hz,yl]nonyl]-4,4-dimethyl- 1H, aryl); 4.33 m(1H, CHOH);5-oxo-2-thioxoimidazolidin- 3.66 m(2H, CH₂N); 2.87 m(1H, CH₂N); 1-yl]-2-2.67 m(1H, CH₂N); 2.49 m(1H, CH₂N); (trifluoromethyl)- 2.42 m(2H, CH₂N);2.26 m(1H, benzonitrile CH₂N); 2.17 m(1H, CH₂); 1.82 m(2H,(S)-Pyrrolidin-3-ol CH₂); 1.72 m(1H, CH₂); 1.58 s(6H, CH₃); 1.49 m(2H,CH₂); 1.31 m(10H, CH₂) 34 4-[4,4-Dimethyl-3-[6-(2- 3 7.95 d(J=8Hz, 1H,aryl); 7.89 d(J=2.1Hz, methylpyrrolidin-1- 1H, aryl); 7.77dd(J=8Hz/2.1Hz, yl)hexyl]-5-oxo-2- 1H, aryl); 3.67 m(2H, CH₂N);thioxoimidazolidin-1- 3.17 m(1H, CH₂N); 2.79 m(1H, CH₂N);yl]-2-(trifluoromethyl)- 2.27 m(1H, CHN); 2.06 m(1H, CH₂N); benzonitrile2.03 m(1H, CH₂N); 2.00-1.35 m(4H, CH₂); 2-Methylpyrrolidine 1.83 m(2H,CH₂); 1.57 s(6H, CH₃); 1.57 m(2H, CH₂); 1.41 m(4H, CH₂); 1.10 d(J=6Hz,3H, CH₃) 35 4-[4,4-Dimethyl-3-[7-(2- 4 7.94 d(J=8Hz, 1H, aryl); 7.89d(J=2.1Hz, methylpyrrolidin-1- 1H, aryl); 7.77 dd(J=8Hz/2.1Hz,yl)heptyl]-5-oxo-2- 1H, aryl); 3.66 m(2H, CH₂N); thioxoimidazolidin-1-3.16 m(1H, CH₂N); 2.78 m(1H, CH₂N); yl]-2-(trifluoromethyl)- 2.24 m(1H,CHN); 2.06 m(1H, CH₂N); benzonitrile 2.02 m(1H, CH₂N); 2.00-1.35 m(4H,CH₂); 2-Methylpyrrolidine 1.82 m(2H, CH₂); 1.57 s(6H, CH₃); 1.52 m(2H,CH₂); 1.38 m(6H, CH₂); 1.10 d(J=6Hz, 3H, CH₃) 364-[4,4-Dimethyl-3-[8-(2- 1 7.94 d(J=8Hz, 1H, aryl); 7.89 d(J=2.1Hz,methylpyrrolidin-1- 1H, aryl); 7.77 dd(J=8Hz/2.1Hz, yl)octyl]-5-oxo-2-1H, aryl); 3.66 m(2H, CH₂N); thioxoimidazolidin-1- 3.16 m(1H, CH₂N);2.77 m(1H, CH₂N); yl]-2-(trifluoromethyl)- 2.25 m(1H, CHN); 2.05 m(1H,CH₂N); benzonitrile 2.03 m(1H, CH₂N); 2.00-1.35 m(4H, CH₂);2-Methylpyrrolidine 1.82 m(2H, CH₂); 1.58 s(6H, CH₃); 1.51 m(2H, CH₂);1.35 m(8H, CH₂); 1.10 d(J=6Hz, 3H, CH₃) 37 4-[3-[8-[(2R,5S)-rel-2,5- 17.95 d(J=8Hz, 1H, aryl); 7.89 d(J=2.1Hz, Dimethylpyrrolidin-1- 1H,aryl); 7.78 dd(J=8Hz/2.1Hz, yl]octyl]-4,4-dimethyl-5- 1H, aryl); 3.67m(2H, CH₂N); oxo-2-thioxoimidazolidin- 2.57 m(2H, CHN); 2.55 m(2H,CH₂N); 1-y1]-2- 1.80 m(2H, CH₂); 1.82 m(2H, CH₂); (trifluoromethyl)-1.58 s(6H, CH₃); 1.46 m(2H, CH₂); benzonitrile 1.30 m(2H, CH₂); 1.35m(8H, CH₂); (2R,5S)-rel-2,5- 1.11 d(J=6Hz, 6H, CH₃) Dimethylpyrrolidine38 4-[3-[6-[(2S)-2-(1- 3 1.12(s, 3H); 1.21(s, b, 3H);Hydroxy-1-methylethyl) 1.30-1.48(b, 4H); 1.58(s, 6H); 1.49-1.95(b, 9H);pyrrolidin-1- 2.33-2.72(b, 3H); 2.73-2.96(b, 1H);yl]hexyl]-4,4-dimethyl- 2.99-3.28(b, 1H); 3.65-3.70(m, 2H);5-oxo-2-thioxoimidazolidin- 7.77(dd, J=2.11Hz, 8.43Hz; 1H); 1-yl]-2-7.89(d, J=1.68Hz; 1H); 7.95(d, J=8.43Hz; (trifluoromethyl)- 1H)benzonitrile (2S)-α-α- Dimethylpyrrolidinemethanol, produced fromL-proline methyl ester according to K. Nakayama, W. J. Thompson, J. Am.Chem. Soc. 112, 6936-6942 (1990) 39 4-[3-[7-[(2S)-2-(1- 4 1.11(s, 3H);1.20(s, b, 3H); Hydroxy-1- 1.30-1.47(b, 6H); 1.58(s, 6H); 1.50-1.92(b,9H); methylethyl)pyrrolidin- 2.35-2.68(b, 3H); 2.70-2.91(b, 1H);1-yl]heptyl]-4,4- 3.00-3.22(b, 1H); 3.64-3.69(m, 2H); dimethyl-5-oxo-2-7.77(dd, J=1.90Hz, 8.26Hz; 1H); thioxoimidazolidin-1- 7.89(d, J=2.10Hz;1H); 7.95(d, J=8.43Hz; yl]-2-(trifluoromethyl)- 1H) benzonitrile(2S)-α,α- Dimethylpyrrolidinemethanol 40 4-[3-[8-[(2S)-2-(1- 1 1.12(s,3H); 1.22(s, b, 3H); Hydroxy-1- 1.27-1.44(b, 8H); 1.58(s, 6H);1.50-1.92(b, 10H); methylethyl)pyrrolidin- 2.36-2.70(b, 2H);2.71-2.95(b, 1H); 1-yl]octyl]-4,4-dimethyl- 3.00-3.23(b, 1H);3.64-3.70(m, 2H); 5-oxo-2-thioxoimidazolidin- 7.77(dd, J=2.11Hz, 8.43Hz;1H); 1-yl]-2- 7.89(d, J=2.11Hz; 1H); 7.95(d, J=8.43Hz;(trifluoromethyl)- 1H) benzonitrile (2S)-α,α-Dimethylpyrrolidinemethanol 41 4-[3-[9-[(2S)-2-(1- 5 1.11(s, 3H);1.18(s, b, 3H); Hydroxy-1- 1.24-1.44(b, 10H); 1.45-1.55(b, 2H); 1.58(s,6H); methylethyl)pyrrolidin- 1.63-1.90(b, 7H); 2.30-3.20(b, 5H);1-yl]nonyl]-4,4- 3.64-3.69(m, 2H); 7.78(dd, J=2.10Hz, dimethyl-5-oxo-2-8.43Hz; 1H); 7.90(d, J=2.53Hz; 1H); thioxoimidazolidin-1- 7.95(d,J=8.01Hz; 1H) yl]-2-(trifluoromethyl)- benzonitrile(2S)-α,α-Dimethylpyrrolidinemethanol 42 4-[3-[6-[(2R)-2-(1- 3 1.10(s,3H); 1.18(s, b, 3H); Hydroxy-1- 1.29-1.47(b, 4H); 1.58(s, 6H);1.48-1.91(b, 9H); methylethyl)pyrrolidin- 2.30-2.65(b, 3H); 2.68-2.92(b,1H); 1-yl]hexyl]-4,4- 2.95-3.18(b, 1H); 3.64-3.70(m, 2H);dimethyl-5-oxo-2- 7.77(dd, J=1.90Hz, 8.01Hz; 1H); thioxoimidazolidin-1-7.89(d, J=1.68Hz; 1H); 7.95(d, J=8.43Hz; yl]-2-(trifluoromethyl)- 1H)benzonitrile (2R)-α,α- Dimethylpyrrolidinemethanol, produced fromD-proline methyl ester according to K. Nakayama, W. J. Thompson, J. Am.Chem. Soc. 112, 6936-6942 (1990) 43 4-[3-[7-[(2R)-2-(1- 4 1.09(s, 3H);1.17(s, b, 3H); Hydroxy-1- 1.29-1.44(b, 6H); 1.58(s, 6H); 1.46-1.90(b,9H); methylethyl)pyrrolidin- 2.33-2.64(b, 3H); 2.68-2.86(b, 1H);1-yl]heptyl]-4,4- 3.97-3.15(b, 1H); 3.64-3.69(m, 2H); dimethyl-5-oxo-2-7.77(dd, J=2.11Hz, 8.01Hz; 1H); thioxoimidazolidin-1- 7.89(d, J=2.10Hz;1H); 7.95(d, J=8.01Hz; yl]-2-(trifluoromethyl)- 1H) benzonitrile(2R)-α,α- Dimethylpyrrolidinemethanol 44 4-[3-[8-[(2R)-2-(1- 1 1.11(s,3H); 1.18(s, b, 3H); Hydroxy-1-methylethyl) 1.23-1.44(b, 8H); 1.58(s,6H); 1.45-1.90(b, 9H); pyrrolidin-1- 2.30-3.15(b, 5H); 3.64-3.69(m, 2H);yl]octyl]-4,4-dimethyl-5- 7.78(dd, J=2.10Hz, 8.43Hz; 1H);oxo-2-thioxoimidazolidin- 7.90(d, J=2.11Hz; 1H); 7.95(d, J=8.43Hz;1-yl]-2- 1H) (trifluoromethyl)- benzonitrile(2R)-α,α-Dimethylpyrrolidinemethanol 45 4-[3-[6-[(2S)-2-(1- 3 0.83(t,J=8.22Hz; 6H); 1.25-1.46(b, Hydroxy-1-ethylpropyl) 6H); 1.59(s, 6H);1.47-1.94(b, 11H); pyrrolidin-1- 2.36-2.56(b, 2H); 2.58-2.77(b, 2H);yl]hexyl]-4,4-dimethyl- 2.87-3.03(b, 1H); 3.64-3.70(m, 2H); 5-oxo-2-7.77(dd, J=2.11Hz, 8.01Hz; 1H); thioxoimidazolidin-1- 7.90(d, J=2.11Hz;1H); 7.95(d, J=8.00Hz; yl]-2-(trifluoromethyl)- 1H) benzonitrile(2S)-α,α-Diethylpyrrolidinemethanol, produced from L-proline methylester according to K. Nakayama, W. J. Thompson, J. Am. Chem. Soc. 112,6936-6942 (1990) 46 4-[3-[7-[(2S)-2-(1- 4 0.80-0.91(m, 6H); 1.22-1.47(b,8H); Hydroxy-1-ethylpropyl)- 1.46-1.95(b, 11H); 1.58(s, 6H);pyrrolidin-1-yl]heptyl]- 2.30-3.30(b, 5H); 3.64-3.70(m, 2H);4,4-dimethyl-5-oxo-2- 7.77(dd, J=2.11Hz, 8.01Hz; 1H); 7.89(d,thioxoimidazolidin-1- J=1.68Hz; 1H); 7.95(d, J=8.01Hz; 1H)yl]-2-(trifluoromethyl)- benzonitrile(2S)-α,α-Diethylpyrrolidinemethanol 47 4-[3-[8-[(2S)-2-(1- 1 0.84(t,J=7.80Hz; 6H); 1.20-1.43(b, Hydroxy-1-ethylpropyl)- 10H); 1.44-1.62(b,4H); 1.59(s, 6H); pyrrolidin-1-yl]octyl]- 1.62-1.90(b, 7H); 2.35-2.56(b,2H); 4,4-dimethyl-5-oxo-2- 2.57-2.76(b, 2H); 2.85-3.04(b, 1H);thioxoimidazolidin-1- 3.64-3.70(m, 2H); 7.78(dd, J=2.32Hz,yl]-2-(trifluoromethyl)- 8.43Hz; 1H); 7.90(d, J=1.68Hz; 1H);benzonitrile 7.95(d, J=8.43Hz; 1H) (2S)-α,α- Diethylpyrrolidinemethanol48 (S)-1-[7-[3-[4-Cyano-3- 4 7.93 d(J=8Hz, 1H, aryl); 7.88 d(J=2.1Hz,(trifluoromethyl) 1H, aryl); 7.77 dd(J=8Hz/2.1Hz, phenyl]-5,5- 1H,aryl); 3.70 s(3H, OCH₃); dimethyl-4-oxo-2- 3.65 m(2H, CH₂N); 3.17 m(1H,CH₂N); thioxoimidazolidin-1- 3.11 dd(J=9Hz/6Hz, 1H, CHN);yl]heptyl]pyrrolidine-2- 2.64 m(1H, CH₂N); 2.33 m(1H, CH₂N); carboxylicacid methyl 2.31 m(1H, CH₂N); 2.09 m(1H, CH₂); ester 1.90 m(2H, CH₂);1.82 m(2H, CH₂); L-Proline methyl ester, 1.80 m(1H, CH₂); 1.56 s(6H,CH₃); Hydrochloride 1.49 m(2H, CH₂); 1.35 m(6H, CH₂) 49(S)-1-[6-[3-[4-Cyano-3- 3 7.95 d(J=8Hz, 1H, aryl); 7.89 d(J=2.1Hz,(trifluoromethyl) 1H, aryl); 7.77 dd(J=8Hz/2.1Hz, phenyl]-5,5- 1H,aryl); 7.22 m(1H, CONH₂); dimethyl-4-oxo-2- 5.61 m(1H, CONH₂); 3.66m(2H, CH₂N); thioxoimidazolidin-1- 3.18 m(1H); 2.99 m(1H); 2.64 m(1H);yl]hexyl]pyrrolidine-4- 2.44 m(1H); 2.28 m(1H); 2.17 m(1H); carboxamide1.83 m(2H, CH₂); 1.80 m(3H, CH₂); L-Prolinamide 1.58 s(6H, CH₃); 1.51m(2H, CH₂); 1.40 m(4H, CH₂) 50 (S)-1-[7-[3-[4-Cyano-3- 4 7.95 d(J=8Hz,1H, aryl); 7.89 d(J=2.1Hz, (trifluoromethyl) 1H, aryl); 7.77dd(J=8Hz/2.1Hz, phenyl]-5,5- 1H, aryl); 7.26 m(1H, CONH₂);dimethyl-4-oxo-2- 5.39 m(1H, CONH₂); 3.66 m(2H, CH₂N);thioxoimidazolidin-1- 3.18 m(1H); 3.00 m(1H); 2.63 m(1H);yl]heptyl]pyrrolidine-4- 2.45 m(1H); 2.30 m(1H); 2.18 m(1H); carboxamide1.89 m(1H, CH₂); 1.81 m(2H, CH₂); L-Prolinamide 1.80 m(2H, CH₂); 1.58s(6H, CH₃); 1.52 m(2H, CH₂); 1.38 m(6H, CH₂) 51 (S)-1-[8-[3-[4-Cyano-3-1 7.95 d(J=8Hz, 1H, aryl); 7.89 d(J=2.1Hz, (trifluoromethyl) 1H, aryl);7.77 dd(J=8Hz/2.1Hz, phenyl]-5,5- 1H, aryl); 7.27 m(1H, CONH₂);dimethyl-4-oxo-2- 5.46 m(1H, CONH₂); 3.66 m(2H, CH₂N);thioxoimidazolidin-1- 3.19 m(1H); 3.00 m(1H); 2.63 m(1H);yl]octyl]pyrrolidine-4- 2.44 m(1H); 2.30 m(1H); 2.18 m(1H); carboxamide1.90 m(1H, CH₂); 1.81 m(3H, CH₂); L-Prolinamide 1.66 m(1H, CH₂); 1.58s(6H, CH₃); 1.49 m(2H, CH₂); 1.35 m(8H, CH₂) 52 (R)-1-[6-[3-[4-Cyano-3-3 7.95 d(J=8Hz, 1H, aryl); 7.89 d(J=2.1Hz, (trifluoromethyl) 1H, aryl);7.77 dd(J=8Hz/2.1Hz, phenyl]-5,5- 1H, aryl); 7.22 m(1H, CONH₂);dimethyl-4-oxo-2- 5.57 m(1H, CONH₂); 3.66 m(2H, CH₂N);thioxoimidazolidin-1- 3.18 m(1H); 2.99 m(1H); 2.64 m(1H);yl]hexyl]pyrrolidine-4- 2.44 m(1H); 2.28 m(1H); 2.17 m(1H); carboxamide1.83 m(2H, CH₂); 1.80 m(3H, CH₂); D-Prolinamide 1.58 s(6H, CH₃); 1.51m(2H, CH₂); 1.40 m(4H, CH₂) 53 (R)-1-[7-[3-[4-Cyano-3- 4 7.95 d(J=8Hz,1H, aryl); 7.89 d(J=2.1Hz, (trifluoromethyl) 1H, aryl); 7.77dd(J=8Hz/2.1Hz, phenyl]-5,5- 1H, aryl); 7.26 m(1H, CONH₂);dimethyl-4-oxo-2- 5.36 m(1H, CONH₂); 3.66 m(2H, CH₂N);thioxoimidazolidin-1- 3.18 m(1H); 3.00 m(1H); 2.63 m(1H);yl]heptyl]pyrrolidine-4- 2.45 m(1H); 2.30 m(1H); 2.18 m(1H); carboxamide1.89 m(1H, CH₂); 1.81 m(2H, CH₂); D-Prolinamide 1.80 m(2H, CH₂); 1.58s(6H, CH₃); 1.52 m(2H, CH₂); 1.38 m(6H, CH₂) 54 (R)-1-[8-[3-[4-Cyano-3-1 7.95 d(J=8Hz, 1H, aryl); 7.89 d(J=2.1Hz, (trifluoromethyl) 1H, aryl);7.77 dd(J=8Hz/2.1Hz, phenyl]-5,5- 1H, aryl); 7.24 m(1H, CONH₂);dimethyl-4-oxo-2- 5.53 m(1H, CONH₂); 3.66 m(2H, CH₂N);thioxoimidazolidin-1- 3.19 m(1H); 3.00 m(1H); 2.63 m(1H);yl]octyl]pyrrolidine-4- 2.44 m(1H); 2.30 m(1H); 2.18 m(1H); carboxamide1.90 m(1H, CH₂); 1.81 m(3H, CH₂); D-Prolinamide 1.66 m(1H, CH₂); 1.58s(6H, CH₃); 1.49 m(2H, CH₂); 1.35 m(8H, CH₂) 55 4-[3-[6-[(2S)-4,4- 31.34-1.49(b, 6H); 1.58(s, 6H); Dimethyl-5-oxo-2- 1.65-1.89(b, 8H);1.90-2.09(b, 2H); (pyrrolidin-1-ylmethyl)- 2.10-2.37(b, 2H);2.38-2.78(b, 7H); pyrrolidin-1-yl]hexyl]-2- 2.84-3.01(b, 1H);3.15-3.26(b, 1H); thioxoimidazolidin-1- 3.64-3.70(m, 2H); 7.77(dd,J=2.11Hz, 8.43Hz; yl]-2-(trifluoromethyl) 1H); 7.89(d, J=1.68Hz; 1H);benzonitrile 7.95(d, J=8.01Hz; 1H) (2S)-2-(Pyrrolidin-1-ylmethyl)pyrrolidine, produced from L-proline according to M. Amedjkouh,P. Ahlberg, Tetrahedron: Asymmetry 13, 2229-2234 (2002) 564-[3-[7-[(2S)-4,4- 4 1.28-1.44(b, 6H); 1.44-1.88(b, 10H);Dimethyl-5-oxo-2- 1.58(s, 6H); 1.89-2.07(b, 2H);(pyrrolidin-1-ylmethyl)- 2.08-2.25(b, 2H); 2.31-2.70(b, 7H);pyrrolidin-1-yl]heptyl]- 2.81-2.93(b, 1H); 3.11-3.21(b, 1H);2-thioxoimidazolidin-1- 3.64-3.69(m, 2H); 7.77(dd, J=2.11Hz, 8.43Hz;yl]-2-(trifluoromethyl) 1H); 7.89(d, J=1.68Hz; 1H); benzonitrile 7.95(d,J=8.43Hz; 1H) (2S)-2-(Pyrrolidin-1- ylmethyl)pyrrolidine 574-[3-[8-[(2S)-4,4- 1 1.22-1.43(b, 8H); 1.48-1.60(b, 2H);Dimethyl-5-oxo-2- 1.58(s, 6H); 1.65-1.87(b, 8H);(pyrrolidin-1-ylmethyl)- 1.92-2.08(b, 2H); 2.09-2.29(b, 2H);pyrrolidin-1-yl]octyl]-2- 2.33-2.62(b, 6H); 2.62-2.76(b, 1H);thioxoimidazolidin-1- 2.80-2.97(b, 1H); 3.11-3.25(b, 1H);yl]-2-(trifluoromethyl) 3.64-3.69(m, 2H); 7.77(dd, J=1.69Hz, 8.01Hz;benzonitrile 1H); 7.89(d, J=1.26Hz; 1H); (2S)-2-(Pyrrolidin-1- 7.95(d,J=8.43Hz; 1H) ylmethyl)pyrrolidine

EXAMPLE 58(S)-1-[7-[3-[4-Cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl]heptyl]pyrrolidine-2-carboxylicacid hydrochloride

20 mg of the compound that is produced under 48 is stirred with aspatula tip full of potassium carbonate in 1 ml of methanol overnight atroom temperature. The reaction mixture is acidified with 4 molar aqueoushydrochloric acid and extracted with ethyl acetate. The orgnaic phase iswashed with saturated sodium chloride solution and concentrated byevaporation in a vacuum. 12 mg of the title compound is obtained.

¹H-NMR (300 MHz, CD₃OD): δ [ppm]=8.15 d (J=8 Hz, 1H, aryl); 8.10 d(J=2.1 Hz, 1H, aryl); 7.93 dd (J=8 Hz/2.1 Hz, 1H, aryl); 3.90 dd (J=9Hz/6 Hz, 1H, CHN); 3.77 m (3H, CH₂N); 3.14 m (1H, CH₂N); 3.26 m (1H,CH₂N); 3.14 m (2H, CH₂N); 2.45 m (1H, CH₂); 2.14 m (2H, CH₂); 1.98 m(1H, CH₂); 1.89 m (2H, CH₂); 1.77 m (2H, CH₂); 1.60 s (6H, CH₃); 1.47 m(6H, CH₂).

1-14. (canceled)
 15. A method for the treatment or prophylaxis of adisease of the human or animal body, which disease can be influenced byinhibition of androgen receptors, comprising administering to a human oranimal in need thereof an effective amount of a pharmaceuticalcomposition comprising a pharmaceutically acceptable adjuvant and/orvehicle and at least one compound of formula I:

in which n means an integer between 6 and 9, R¹ and R², independently ofone another, mean a hydrogen atom, an unbranched C₁-C₄-alkyl group, abranched C₃-C₅-alkyl group, an unbranched hydroxy-C₁-C₄-alkyl group, abranched hydroxy-C₃-C₅-alkyl group, an unbranchedC₁-C₄-alkoxy-C₁-C₄-alkyl group, a branched C₁-C₄-alkoxy-C₃-C₅-alkylgroup, an unbranched C₁-C₄-alkanoyloxy-C₁-C₄-alkyl group, a branchedC₁-C₄-alkanoyloxy-C₃-C₅-alkyl group, a (pyrrolidin-1-yl)methyl group, acarboxy group, a C₁-C₄-alkoxycarbonyl group or an aminocarbonyl group,or R¹ and R² together mean a 2-hydroxypropane-1,3-diyl bridge; R³ meansa hydrogen atom or a hydroxy group, or a pharmacologically acceptablesalt thereof.
 16. A method according to claim 15, wherein the disease isan androgen-dependent proliferative disease.
 17. A method according toclaim 15, wherein the disease treated is a tumor disease.
 18. A methodaccording to claim 15, wherein the disease treated is prostate cancer.19. A method according to claim 15, wherein the disease is anandrogen-dependent non-proliferative disease.
 20. A method according toclaim 15, wherein the disease is androgenetic alopecia, hirsutism oracne.
 21. A method according to claim 15, wherein the disease is benignprostate hyperplasia.
 22. A method according to claim 15, wherein in thecompound of formula I R¹ represents a hydrogen atom, a hydroxymethylgroup, an aminocarbonyl group or a methoxymethyl group; R² and R³ ineach case represent a hydrogen atom.
 23. A method according to claim 15,wherein in the compound of formula I R¹ represents a hydrogen atom, or amethyl group; and R² and R³ in each case represent a hydrogen atom. 24.A method according to claim 15, wherein in the compound of formula I R¹and R² together represent a 2-hydroxypropane-1,3-diyl bridge; and R³represents a hydrogen atom.
 25. A method according to claim 15, whereinthe compound of formula I is4-[4,4-Dimethyl-5-oxo-3-[8-(pyrrolidin-1-yl)octyl]-2-thioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile4-[4,4-Dimethyl-5-oxo-3-[8-(pyrrolidin-1-yl)octyl]-2-thioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrilehydrochloride4-[4,4-Dimethyl-5-oxo-3-[6-(pyrrolidin-1-yl)hexyl]-2-thioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile4-[4,4-Dimethyl-5-oxo-3-[7-(pyrrolidin-1-yl)heptyl]-2-thioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile4-[4,4-Dimethyl-5-oxo-3-[9-(pyrrolidin-1-yl)nonyl]-2-thioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile4-[3-[6-[(2R)-2-(Hydroxymethyl)pyrrolidin-1-yl]hexyl]-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile4-[3-[6-[(2S)-2-(Hydroxymethyl)pyrrolidin-1-yl]hexyl]-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile4-[3-[7-[(2R)-2-(Hydroxymethyl)pyrrolidin-1-yl]heptyl]-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile4-[3-[7-[(2S)-2-(Hydroxymethyl)pyrrolidin-1-yl]heptyl]-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile4-[3-[8-[(2R)-2-(Hydroxymethyl)pyrrolidin-1-yl]octyl]-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile4-[3-[8-[(2S)-2-(Hydroxymethyl)pyrrolidin-1-yl]octyl]-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile4-[3-[9-[(2R)-2-(Hydroxymethyl)pyrrolidin-1-yl]nonyl]-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile4-[3-[9-[(2S)-2-(Hydroxymethyl)pyrrolidin-1-yl]nonyl]-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile4-[3-[6-[(2R)-2-(Methoxymethyl)pyrrolidin-1-yl]hexyl]-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile4-[3-[6-[(2S)-2-(Methoxymethyl)pyrrolidin-1-yl]hexyl]-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile4-[3-[7-[(2R)-2-(Methoxymethyl)pyrrolidin-1-yl]heptyl]-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile4-[3-[7-[(2S)-2-(Methoxymethyl)pyrrolidin-1-yl]heptyl]-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile4-[3-[8-[(2R)-2-(Methoxymethyl)pyrrolidin-1-yl]octyl]-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile4-[3-[8-[(2S)-2-(Methoxymethyl)pyrrolidin-1-yl]octyl]-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile4-[3-[9-[(2R)-2-(Methoxymethyl)pyrrolidin-1-yl]nonyl]-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile4-[3-[9-[(2S)-2-(Methoxymethyl)pyrrolidin-1-yl]nonyl]-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile4-[3-[6-(3-Hydroxy-8-azabicyclo[3.2.1]oct-8-yl)hexyl]-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile4-[3-[7-(3-Hydroxy-8-azabicyclo[3.2.1]oct-8-yl)heptyl]-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile4-[3-[8-(3-Hydroxy-8-azabicyclo[3.2.1]oct-8-yl)octyl]-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile4-[3-[9-(3-Hydroxy-8-azabicyclo[3.2.1]oct-8-yl)nonyl]-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile4-[3-[6-[(R)-3-Hydroxypyrrolidin-1-yl]hexyl]-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile4-[3-[7-[(R)-3-Hydroxypyrrolidin-1-yl]heptyl]-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile4-[3-[8-[(R)-3-Hydroxypyrrolidin-1-yl]octyl]-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile4-[3-[9-[(R)-3-Hydroxypyrrolidin-1-yl]nonyl]-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile4-[3-[6-[(S)-3-Hydroxypyrrolidin-1-yl]hexyl]-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile4-[3-[7-[(S)-3-Hydroxypyrrolidin-1-yl]heptyl]-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile4-[3-[8-[(S)-3-Hydroxypyrrolidin-1-yl]octyl]-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile4-[3-[9-[(S)-3-Hydroxypyrrolidin-1-yl]nonyl]-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile4-[4,4-Dimethyl-3-[6-(2-methylpyrrolidin-1-yl)hexyl]-5-oxo-2-thioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile4-[4,4-Dimethyl-3-[7-(2-methylpyrrolidin-1-yl)heptyl]-5-oxo-2-thioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile-4-[4,4-Dimethyl-3-[8-(2-methylpyrrolidin-1-yl)octyl]-5-oxo-2-thioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile4-[3-[8-[(2R,5S)-rel-2,5-Dimethylpyrrolidin-1-yl]octyl]-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile4-[3-[6-[(2S)-2-(1-Hydroxy-1-methylethyl)pyrrolidin-1-yl]hexyl]-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile4-[3-[7-[(2S)-2-(1-Hydroxy-1-methylethyl)pyrrolidin-1-yl]heptyl]-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile4-[3-[8-[(2S)-2-(1-Hydroxy-1-methylethyl)pyrrolidin-1-yl]octyl]-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile4-[3-[9-[(2S)-2-(1-Hydroxy-1-methylethyl)pyrrolidin-1-yl]nonyl]-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile4-[3-[6-[(2R)-2-(1-Hydroxy-1-methylethyl)pyrrolidin-1-yl]hexyl]-4,4-dimethy-5-oxo-2-thioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile4-[3-[7-[(2R)-2-(1-Hydroxy-1-methylethyl)pyrrolidin-1-yl]heptyl]-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile4-[3-[8-[(2R)-2-(1-Hydroxy-1-methylethyl)pyrrolidin-1-yl]octyl]-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile4-[3-[6-[(2S)-2-(1-Hydroxy-1-ethylpropyl)pyrrolidin-1-yl]hexyl]-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile4-[3-[7-[(2S)-2-(1-Hydroxy-1-ethylpropyl)pyrrolidin-1-yl]heptyl]-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile4-[3-[8-[(2S)-2-(1-Hydroxy-1-ethylpropyl)pyrrolidin-1-yl]octyl]-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile(S)-1-[7-[3-[4-Cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl]heptyl]pyrrolidine-2-carboxylicacid methyl ester(S)-1-[6-[3-[4-Cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl]hexyl]pyrrolidine-4-carboxamide(S)-1-[7-[3-[4-Cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl]heptyl]pyrrolidine-4-carboxamide(S)-1-[8-[3-[4-Cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl]octyl]pyrrolidine-4-carboxamide(R)-1-[6-[3-[4-Cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl]hexyl]pyrrolidine-4-carboxamide(R)-1-[7-[3-[4-Cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl]heptyl]pyrrolidine-4-carboxamide(R)-1-[8-[3-[4-Cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl]octyl]pyrrolidine-4-carboxamide4-[3-[6-[(2S)-4,4-Dimethyl-5-oxo-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]hexyl]-2-thioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile4-[3-[7-[(2S)-4,4-Dimethyl-5-oxo-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]heptyl]-2-thioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile4-[3-[8-[(2S)-4,4-Dimethyl-5-oxo-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]octyl]-2-thioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrileor(S)-1-[7-[3-[4-Cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl]heptyl]pyrrolidine-2-carboxylicacid hydrochloride.